Cellular & Molecular (2013) 10, 50–57 ß 2013 CSI and USTC. All rights reserved 1672-7681/13 $32.00 www.nature.com/cmi

REVIEW cd-T cells: an unpolished sword in human anti-infection

Jian Zheng, Yinping Liu, Yu-Lung Lau and Wenwei Tu cd-T cells represent a small population of immune cells, but play an indispensable role in host defenses against exogenous pathogens, immune surveillance of endogenous pathogenesis and even of the . Activation and expansion of cd-T cells are generally observed in diverse human infectious diseases and correlate with their progression and prognosis. cd-T cells have both ‘innate’ and ‘adaptive’ characteristics in the immune response, and their anti-infection activities are mediated by multiple pathways that are under elaborate regulation by other immune components. In this review, we summarize the current state of the literature and the recent advancements in cd--mediated immune responses against common human infectious pathogens. Although further investigation is needed to improve our understanding of the characteristics of different cd-T cell subpopulations under specific conditions, cd-T cell-based therapy has great potential for the treatment of infectious diseases. Cellular & Molecular Immunology (2013) 10, 50–57; doi:10.1038/cmi.2012.43; published online 15 October 2012

Keywords: cd-T cells; infection; immunity; human

INTRODUCTION skin cd-T cells promote tissue repair by producing keratinocyte growth Infectious disease is one of the major threats to human health and causes factor.8 On the other hand, some cd-T cells, especially IL-17-producing substantial global morbidity and mortality. Current strategies for con- cd-T cells, have been confirmed to be involved in the pathogenesis of trolling infection principally focus on the pathogens themselves, but transplantation rejection,9 autoimmune diseases,10–13 inflammatory neglect the importance of the host factors that are involved in the process diseases14,15 and allergy16 in human and animal models. However, of disease.1 However, the rapid emergence of drug resistance in infec- the scarcity of peripheral cd-T cells and the difficulties in monitoring tious pathogens often leads to costly therapy that is largely ineffective. their fate in vivo make it difficult to achieve a comprehensive under- Moreover, the efficiency of the adaptive immune response induced by standing of the characteristics of human cd-T cells. Thus, the general vaccines might be significantly impaired by the rapid immune evasion of application of cd-T cell-based immune therapy in treating infectious pathogens through their frequent mutations. To this extent, innate diseases still needs further support from experimental investigations. immune cells that recognize the conserved structural components of In this review, we will focus on the roles of human cd-T cells in anti- pathogens and raise rapid responses against the dangerous signals infection immunity. With insights into the underlying mechanisms and evoked by infections have great potential in anti-infection therapy. regulation of the cd-T cell-mediated anti-infection immune responses, Human cd-T cells are critical components of the innate immune this review is expected to provide perspective on the development of cd- system and play critical roles in the early response to invasive pathogens. T cell-based immune therapy against infectious diseases in the future. cd-T cells represent only a minor T-cell population in peripheral (2%–10% of CD31 T cells), but constitute the major subset of resident T ROLES OF cd-T CELLS IN INFECTIOUS DISEASES cells in mucosa and skin.2 This preferential distribution favors their Subpopulations of human cd-T cells initial in situ anti-infection activities. Compared with the T-cell receptors Human cd-T cells can be classified into two main populations accor- (TCRs) of conventional ab-T cells, the TCRs of cd-T cells are relatively ding to their TCR expression, which is determined early in the invariant and the exact ligands they recognize are still unknown.3 through TCR-mediated selection:17 Vd1 and Vd2 cd-T cells. Vd1 cd-T Nevertheless, it has been confirmed that cd TCRs can sense the evolu- cells are abundant in the skin, epithelia, intestine and uterus; in con- tionarily conserved components of exogenous pathogens as unique trast, Vd2 cd-T cells are the majority of peripheral blood cd-T cells.18 receptor agonists and initiate a rapid response against them.4,5 Consistent with their different distributions, these two cd-T2cell The roles of cd-T cells are multifaceted and correlate with their subpopulations also exhibit distinct migratory patterns and homing distribution and differentiation.2 Ontheonehand,epidermalcd-T cells capabilities.17 play an indispensable role in limiting and eliminating invasive patho- Although it is still controversial whether cd-T cells are capable of gens and recruiting inflammatory cells to infected locations,6,7 while -specific memory in the same manner as ab-T cells, the

Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China Correspondence: Dr WW Tu, Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Room L7-56, 7/F Laboratory Block, Faculty of Medicine Bldg, 21 Sassoon Rd, Hong Kong SAR, China. E-mail: [email protected] ([email protected]) Received 19 July 2012; accepted 28 August 2012 cd-T cells in anti-infection immunity J Zheng et al 51 memory and activation markers CD27 and CD45RA have been found immune system during in utero infection, which offers protection in to be expressed on cd-T cells.19,20 Similarly to ab-T cells, cd-T cells can early life.36 Similarly, cd-T cells also exhibit beneficial roles in con- also be classified into four populations based on their expression of trolling HIV infection.24 cd-T cells in HIV-infected patients have been CD27 and CD45RA: naive (CD271CD45RA1), effector memory found to exhibit antiviral potential through their cell-lytic functions37 (CD272CD45RA2), central memory (CD271CD45RA2) and ter- and secretions.38 Although the quantity and quality of cd-T minally differentiated (CD272CD45RA1).21 More important, subpo- cells have been found to generally decrease with the advancement of pulations of cd-T cells identified by the expressions of CD27 and HIV infection,39 the suppressed functions of Vc9Vd2 cd-T cells can be CD45RA exhibit unique functions during mycobacterial infection that enhanced by stimulation with phosphoantigen,39 which might correspond to the functions of their ab-T cell analogues.21 In addition become a novel target of therapeutic strategies. to these two markers, other surface makers are also detected to identify cd-T cells also help control the infection caused by Epstein–Barr cd-T cells of different characteristics. Our recent study demonstrated virus40 and human hepatitis virus C41 in humans. However, the activa- that human CD561 Vd2 cd-T cells have a higher cytolytic capacity tion of cd-T cells by hepatitis virus C might induce excessive inflam- against influenza virus-infected cells than CD562 Vd2 cd-T cells, sug- mation and result in severe side effects.41 In addition, activated cd-T gesting that the expression of CD56 might be a marker for subsets of cells can improve ab-T cell-mediated specific immune responses cd-T cells that protect against infection.22 against Epstein–Barr virus-induced lymphoma42 and contribute to the suppression of polyomavirus-induced tumor growth.43 Involvement of cd-T cells in infectious diseases The dynamic variation in the quality and quantity of human cd-T cells Bacteria. Human cd-T cells can recognize multiple conserved patho- affects the initiation, progression and prognosis of infectious diseases. gen and raise rapid immune responses. Although they have Similarly, the nature of the pathogen affects the response of cd-T cells. been found to participate in immune responses during many infec- 44 The exact roles of cd-T-cell subpopulations during infections are tions, including , , legionellosis, , 45 dependent on their distinct functions and on the specific pathogens. listeriolisis and Escherichia coli infections, the importance of human In the following section, we provide an overview of the involvement of cd-T cells in anti-bacterial activity is still controversial because the cd-T cells during infection with different pathogens. complicated immune responses initiated by the diverse components and products of bacteria make it difficult to identify the independent Viruses. Although the mechanisms underlying cd-T cell-mediated roles of cd-T cells. Recently, successful control of both extracellular immune responses against viruses are still incompletely understood, Gram-positive (Staphylococcus aureus) and Gram-negative (E. coli and their protective effects have been confirmed in several acute and Morganella morganii) bacterial infections in severe combined immu- nodeficiency mice by adoptive transfer of human Vc9Vd2 cd-T cells chronic viral infections. The activation and cytokine secretions of 46 cd-T cells are regarded as indicators of early viral infection.23,24 offers solid evidence of the potent protective functions of cd-T cells. Similarly to the contribution of murine cd-T cells during recovery More importantly, some intracellular bacterial pathogens, such as 25 , can specifically expand and activate after influenza-caused pneumonia, the beneficial effects of human Vc9Vd2 cd-T cells by inducing the production of metabolites (e.g., Vc9Vd2 cd-T cells against influenza virus infection have also recently isopentenyl pyrophosphate, IPP) in infected cells, which strongly sug- been confirmed by our laboratory.22,26,27 Through the direct killing of gests the importance of cd-T cells in infection control.47 Consistent virus-infected cells and the production of antiviral , Vc9Vd2 with this finding, the suppression of cd-T cells by chronic tuberculosis cd-T cells can control infection by different strains of the influenza infection can result in a disastrous outcome.48 virus, such as human seasonal H1N1, pandemic H1N1, and the avian H5N1 and H9N2 viruses.22,26,27 Moreover, these antiviral activities can be significantly improved by phosphoantigen stimulation, which Other infectious pathogens. In addition to their protective functions in confers sufficient protection on humanized mice to prevent lethal viral and bacterial infections, cd-T cells have been found to be acti- 49 influenza virus infection.28 In addition, another group has shown that vated and to help control infections caused by Leishmania and 50 cd Toxoplasma gondii, although the cd-T cell-mediated -T cells can initiate efficient adaptive immunity through processing 50 and presenting influenza virus-derived to CD41 and CD81 T also causes some unwanted destruction of surrounding tissue. 29 cd Similarly, the protective roles of cd-T cells in infection have cells. Moreover, -T cells have been found to promote the estab- 51,52 lishment of protective adaptive immunity against West Nile virus by been confirmed in several independent studies. inducing the maturation of dendritic cells (DCs).30 However, the pro- tective functions of cd-T cells can be impaired by some viruses. It has HOW DO cd-T CELLS SENSE INFECTIOUS PATHOGENS? been shown that herpes simplex virus31 and respiratory syncytial Despite their active roles in diverse human infectious diseases, the virus32 can directly infect local or peripheral cd-T-cell subsets, respec- pathways that are used by cd-T cells to sense pathogens and initiate tively, which results in their dysfunction, although a few protective rapid responses remain largely unknown. In this section, we will virus-reactive cd-T cells could still be detected in patients infected with explore some of the principal signals that are critical for cd-T cell- herpes simplex virus.33 mediated anti-infection activity. The protective roles of cd-T cells have also been confirmed in some chronic infectious diseases. Vd22 cd-T cells, the minor subpopulation Host cell-derived signals of peripheral blood cd-T cells, have been found to expand on a large It is generally accepted that most factors that sensitize cd-T cells ori- scale during human (HCMV) infection.34 These ginate from host cells rather than from pathogens themselves.23 HCMV-reactive Vd22 cd-T cells have a more potent ‘virus-specific’ Although the ligands for cd TCRs are still elusive, some molecules than their Vd21 analogues and show increased elimina- belonging to the phosphoantigen family have been extensively inves- tion of pathogens.35 More importantly, this Vd22 cd-T cell-mediated tigated for their application in activating cd-T cells based on their ‘HCMV-specific immune response’ can be induced in the fetal specific recognition by Vc9Vd2 TCRs. These phosphoantigens are

Cellular & Molecular Immunology cd-T cells in anti-infection immunity J Zheng et al 52

usually natural metabolites of isoprenoid biosynthesis in host cells, some heat shock proteins,85,89 which undoubtedly improves the which include IPP, (E)-4-hydroxy-3-methyl-but-2-enyl pyropho- efficiency of cd-T cell-mediated immune responses during the very sphate, dimethylallyl pyrophosphate (DMAPP)53,54 and bromohydrin early phases of infections without the need to interact with APCs. pyrophosphate.55 These phosphoantigens can be presented by T cells, Finally, there are still debates regarding whether cd-T cells also possess and various antigen-presenting cells (APCs), such as DCs antigen specificity similar to ab-T cells, although rapid recall expan- and B cells,56,57 through expression of CD1d58,59 and as-yet unknown sions of clonotypic cd-T cells have been found in mycobacterial90 and non-MHC molecules on host cells.60 The clinical applications of phos- monocytogenes53 infections. A recent investigation demon- phoantigens in cd-T cell-based therapy will be discussed in a later part strating receptor selection in peripheral cd-T cells supported the exist- of this review. ence of antigen-specific memory in human cd-T cells.91 However, care Similarly to ab-T cells, cd-T cells also need secondary signals that should be taken when identifying ‘antigen-specific cd-T cells’ before are provided by costimulatory molecules to achieve expansion and clarifying whether these ‘memory-like responses’ are antigen-restricted 92 optimal activation.61,62 Many costimulators, such as CD2,63 or presenting molecule-restricted. For example, the CD1d agonist a- CD2864,65 and CD137 (4-1BB),66 are expressed in human cd-T cells GalCer can independently induce interferon (IFN)-c production by 93 and help to promote their activation. On the contrary, when the cd-T cells regardless of the presenting capability of CD1d, which inhibitory molecule programmed death 1 was expressed in cd-T cells, does not classically belong as an antigen-specific immune response. it was found to suppress their expansion through interaction with its ligand when the ligand was expressed on infected cells or tumor- cd-T CELL-MEDIATED ANTI-INFECTION IMMUNITY related cells (Daniel Oliver, personal communication). In addition After being sensitized by danger signals derived from pathogens or to their roles during activation or inhibition of cd-T cells, costimula- host cells, cd-T cells execute their anti-infection activities through cd tors can modify the differentiation of -T cells. For example, the multiple pathways. Additionally, the cd-T cell-mediated immune res- inducible costimulator–inducible costimulator ligand interaction ponses are tightly controlled by multiple intrinsic and extrinsic factors, has been found to arm cd-T cells with some of the properties of 67 which guarantee the high efficiency of the immune responses and follicular T cells and thus assist in production by B cells. reduce unwanted destruction caused by excessive inflammation. In addition to the conventional costimulators that are shared with ab- T cells, several novel molecules can serve as the secondary signals for the activation of cd-T cells. It has been found that the expression of Direct anti-infection activity mediated by cd-T cells junctional adhesion molecule-like protein68 and high-mobility group Direct killing of infected cells or infectious pathogens is the most box 169 by cd-T cells provides positive signals for the activation of cd- prominent mechanism of the cd-T cell-mediated anti-infection res- T cells, whereas stimulation with E-cadherin downregulates their ponses. cd-T cell-mediated cytotoxicity is carried out through dozens functions.70 The natural killer (NK) cell receptor family is another of pathways, including Fas–Fas ligand interaction and secretion of 27 94 important group of costimulators for regulating the activity of cd-T perforin, granzyme B and granzyme M. In contrast to the cyto- 22 cells, and the balance among stimulatory and inhibitory natural killer toxicity of NK cells, the cytotoxicity mediated by Vc9Vd2 cd-T cells 2 34 WW (NK) cell receptor signals might determine the functions of cd-T and Vd2 cd-T cells against influenza virus- and HCMV-infected cells. For example, NKG2D and NKG2C promote the activation of cd- cells can be initiated independent of the antibody-dependent cell- T cells, whereas NKG2A transfers inhibitory signals to them.71–73 mediated cytotoxicity effect. Consistent with this mechanism, the Fc receptor CD16, a key player in antibody-dependent cell-mediated cytotoxicity, has been shown to improve the anti-viral activity of Pathogen-related antigens Vd22 cd-T cells by inducing them to produce IFN-c during HCMV Human cd-T cells also recognize danger signals derived directly from infection.95 pathogens. Toll-like receptors (TLRs) are the most important patho- In addition to their cytotoxic capacities, cd-T cells are able to secrete gen recognition receptors and are capable of recognizing a broad dozens of potent soluble pro-inflammatory molecules and directly spectrum of pathogen-associated molecule patterns from infectious attack infectious pathogens. Similarly to its role in HCMV infection, pathogens. TLRs play critical roles in the antiviral activities of cd-T IFN-c secreted from Vc9Vd2 cd-T cells inhibits influenza virus pro- cells.74 The expression of TLRs in resting cd-T cells is usually weak or pagation.26 In addition, IL-17 and tumor-necrosis factor-a secreted by undetectable but can be quickly upregulated in activated cd-T cells. It various cd-T cell populations contribute to the control and elimina- has been found that activated cd-T cells express nearly all TLRs, tion of several types of bacteria45,96 and Plasmodium falciparum.51 although the expression levels of different TLRs are distinct in dif- Recently, IL-22 has been suggested as a potent anti-infection cytokine ferent subsets.74 For example, both Vd275 and Vd176 cd-T cells can in the cd-T cell-mediated anti-infection immune response by some be activated by TLR4 and TLR5 ligands and exhibit increased anti- reports.97,98 bacteria responses, whereas the specific expression of TLR3 in Vd2 cd- T cells favors their stimulation through this pathway.74 Moreover, pan-cd-T cells can be activated77 through stimulation of the hetero- Indirect anti-infection activity mediated by cd-T cells dimers TLR1/2 and TLR2/6 with a mixture of TLR2 ligands, while the Initiating local immune responses. Local responses aroused during the production of Th1 cytokines and the cytolytic activity of cd-T cells can early phase of infection are crucial for limiting the spread of patho- be enhanced by stimulation with double-stranded RNA78 and DNA79 gens. Both resident and circulating cd-T cells accumulate quickly through TLR3 and TLR9, respectively, during viral infections. around invasive pathogens and induce efficient anti-infection res- In addition to TLRs, cd TCRs can induce the anti-infection activity ponses through collaboration with neighboring immune cells.99 cd- of cd-T cells by recognizing multiple pathogen-derived peptides80–82 T cells enhance the anti-infection capabilities of resident and unprocessed pathogen-related proteins such as tetanus toxoid,83 and NK cells,100,101 promote the maturation of DCs6,102 and improve herpes simplex virus I,84 mycobacterial purified protein the invasion resistance of epithelial cells.103,104 Importantly, the derivatives,85,86 staphylococcal enterotoxin A,87 listeriolysin O88 and dynamic interaction between cd-T cells and their neighbors induces

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TCR selection of cd-T cells in situ, leading to more precise responses accompanied by IL-17 and IL-22, has also been found to contribute against specific pathogens.101,103 Similarly to other sentinel cells, cd-T to the activation and expansion of cd-T cells during M. tuberculosis53 cells also secrete such as CCL2, CCL3 and CCL4 to recruit infection. A similar effect that is mediated by IL-23 has been found in pro-inflammatory to accelerate the elimination of patho- Listeria monocytogenes128 infection as well. In addition, IL-7,129 IL- gens and the repair of damaged tissues.26 21130 and the caspase-1-processed IL-1 family cytokines IL-1b and IL-18131 increase the anti-infection ability of cd-T cells by promoting APC function. In addition to their direct anti-infection activities, expansion and cytokine production. Moreover, IFN-c has been found human cd-T cells act as professional APCs and take up, process and to contribute to the antagonizing effects of cd-T cells against regu- 132 present pathogen-related antigens from both free viral particles29 and lation that is mediated by Tregs. In contrast, type I IFN has been infected cells57,105 to other effector immune cells.106,107 These cd-T found to constrain IL-17A production by cd-T cells against Francisella 133 APCs express approximately similar levels of HLA-DR and CD80/ tularensis subspecies novicida, while administration of either trans- 134 135 CD86 compared to traditional APCs29 and induce NK cell activa- forming growth factor-b or IL-10 alone inhibits IFN-c produc- tion,108,109 antigen-specific ab-T-cell responses29,107 and even anti- tion by cd-T cells in response to mycobacterial infection. The body production.67 Although the physiological roles of cd-T APCs administration of transforming growth factor-b accompanied by still need to be illuminated by more in vivo studies, recent investi- anti-cd TCR can even induce human and murine cd-T cells into a 119,120 gations of murine cd-T cells have confirmed the general existence of regulatory status, thus dampening their anti-infection effects. cd-T APCs.110 Chemokines are another important group of soluble factors that determine the outcome of cd-T cell-mediated anti-infection immune responses. It has been found that RANTES, MIP1a/b and CXCL9/10/ Modifying adaptive immunity. Although generally regarded as a com- 26 ponent of the based on their invariant TCRs 11 secreted from infected cells guide the migration of CCR5 - and 136 c d cd and rapid responses to danger signals, cd-T cells are now accepted as a CXCR3 - expressed IPP-activated V 9V 2 -T cells to influenza- 111 infected sites and facilitate the elimination of pathogens. crucial player in the as well. The contri- bution of cd-T cells to adaptive immunity goes beyond their APC function mentioned above. For example, cd-T cells are capable of POTENTIAL OF cd-T CELL-BASED THERAPY IN INFECTIOUS inducing the maturation of DCs,67 facilitating the development of DISEASES 13,112 113,114 ab-T cells, killing regulatory T cells (Tregs) and migrating Obstacles to the application of cd-T cell-based therapy into the secondary lymphoid tissues and acting as follicular B helper T Current investigations on human cd-T cells offer a promising future 115,116 cells to promote antibody production. Moreover, cd-T cells can for infectious disease therapeutic strategies, although many questions compete with ab-T cells for growth factors such as IL-15 and thus that need to be answered remain before general application in the 117 modify the adaptive immune response. clinic will be possible. One major obstacle to cd-T cell-based therapy is the scarcity of cd-T cells in peripheral blood. Although phosphoan- Treg function. cd-T cells have also been found to exhibit several ‘re- tigens have been globally applied in the expansion of Vc9Vd2 cd-T gulatory characteristics’ in both humans and mice.118,119 Similarly to cells, the in vivo effects of these drugs need to be thoroughly investi- conventional CD41 Tregs, a regulatory Vd1 cd-T cell subset identified gated. Another impediment to studying the efficacy of phosphoanti- by the expression of CD27 and CD25 in the peripheral blood of sys- gen activation and expansion of Vc9Vd2 cd-T cells is the lack of an temic lupus erythematosus patients has been found to correlate with analogue in murine systems, which can be overcome by the develop- the progression and remission of the disease.120 Moreover, IPP- ment of a humanized mouse model.28,137 Similarly, reliable animal induced Vc9Vd2 cd-T-cell expansion has been found models need to be established for evaluating the characteristics and to ameliorate arthritis.121 However, the contribution of these regula- clinical potential of human resident cd-T cells in mucosa and skin. tory cd-T cells to anti-infection responses is still unclear. Current strategies for activating or expanding cd-T cells Regulation of cd-T-mediated anti-infection responses The approach of using phosphoantigens plus IL-2 has been the most The immune system is equipped with an elaborate regulatory network, potent and widely accepted protocol for activation and expansion of which guarantees its efficiency while avoiding the unnecessary Vc9Vd2 cd-T cells both in vitro and in vivo.138 For adoptive transfer destruction caused by immune responses. In the battle against infec- therapy, a single dose as large as 109 ex vivo expanded Vc9Vd2 cd-T tious pathogens, the activity of cd-T cells is also regulated by other cells has been confirmed to be safe by several independent investi- molecules that act through multiple pathways. It has been confirmed gations.139–141 Encouragingly, these infused Vc9Vd2 cd-T cells exhib- that both murine122 and human123 CD41 Tregs can directly suppress ited satisfactory clinical benefit in an anti-tumor trial.142 For in vivo the expansion and cytokine production of mucosal cd-T cells, whereas applications, a single dose of (E)-4-hydroxy-3-methyl-but-2-enyl pyr- effector CD41 T cells help maintain IL-17 production in cd-T cells in ophosphate plus 5 days of IL-2 treatment induced an 80-fold expan- naive animals.124 These dynamic interactions exist not only between sion of macaque peripheral blood Vc9Vd2 cd-T cells without adaptive immunity and innate immunity, but also within the innate detectable side effects.143 More excitingly, the administration of (E)- immune system itself. For example, NK cells can exhibit inhibitory 4-hydroxy-3-methyl-but-2-enyl pyrophosphate and IL-2 was con- effects on the activation and cytotoxicity of cd-T cells and protect firmed to significantly induce prolonged accumulation of Vc9Vd2 pregnant women from preeclampsia.125 cd-T cells in the lungs of cynomolgus monkeys and ameliorate lung In addition to cellular regulation, the development, proliferation lesions caused by Yersinia pestis infection.144 Presently, bisphospho- and activation of cd-T cells in anti-infection immune responses are nates such as Pamidronate and Zoledronate145 are ‘old’ drugs that are also controlled by multiple soluble molecules, in particular cytokines. routinely applied in treating or Paget’s disease and have Similarly to NK cells, both IL-7 and IL-15 are indispensable during shown potential benefits in human tumor therapies146–148 and for the development and homeostasis of cd-T cells,126 while IL-15,127 treating influenza infection in humanized mice.28

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In addition to phosphoantigens, stimulation that targets TLRs, 2 Born WK, Reardon CL, O’Brien RL. The function of gammadelta T cells in innate immunity. Curr Opin Immunol 2006; 18: 31–38. natural killer (NK) cell receptors or CD3 have also been applied in the 3 Xi X Guo Y, Chen H, Xu CP, Zhang HY, Hu HB et al. Antigen specificity of gamma delta T activation and expansion of pan-cd-T cells in vitro.149 In line with these cells primarily depends on the flanking sequences of CDR3 delta. J Biol Chem 2009; efforts, significant outcomes have been claimed for the usage of anti-cd 284: 27449–27455. 4 Hayday AC. cd cells: a right time and a right place for a conserved third way of TCR antibody accompanied by cytokines in expanding human cd-T protection. Annu Rev Immunol 2000; 18: 975–1026. cells,150 which improved the treatment of tumors in a mouse model151 5 Kabelitz D, Glatzel A, Wesch D. Antigen recognition by human gammadelta T 120 . Int Arch Immunol 2000; 122: 1–7. andhelpedameliorateautoimmune diseases. Nevertheless, the effica- 6 Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR et al. IL-17 is cies of these distinct protocols need to be evaluated and compared under essential for host defense against cutaneous Staphylococcus aureus infection in mice. standard conditions to achieve the optimal therapeutic effect. Moreover, J Clin Invest 2010; 120: 1762–1773. 7 Molne L, Corthay A, Holmdahl R, Tarkowski A. Role of gamma/delta T cell receptor- the associated changes in the phenotypes of these accumulated cd-T cells expressing lymphocytes in cutaneous infection caused by Staphylococcus aureus. need to be clarified before their clinical application. Clin Exp Immunol 2003; 132: 209–215. 8 Jameson J, Ugarte K, Chen N, Yachi P, Fuchs E, Boismenu R et al. A role for skin gammadelta T cells in wound repair. Science 2002; 296: 747–749. Prospective and potential limitations 9 Shiohara T, Moriya N, Hayakawa J, Itohara S, Ishikawa H. Resistance to cutaneous The application of cd-T cell-based therapy against infectious diseases graft-vs.-host disease is not induced in T cell receptor delta gene-mutant mice. J Exp Med 1996; 183: 1483–1489. has a bright future. One of its most prominent advantages comes from 10 Ferri S, Longhi MS, de Molo C, Lalanne C, Muratori P, Granito A et al. A multifaceted the recognition of danger signals rather than of pathogens themselves, imbalance of T cells with regulatory function characterizes type 1 autoimmune which can engage in immune evasion through frequent mutation of hepatitis. Hepatology 2010; 52: 999–1007. 23 11 Ito Y, Usui T, Kobayashi S, Iguchi-Hashimoto M, Ito H, Yoshitomi H et al. Gamma/delta . Another advantage of cd-T cell-based therapy relies on T cells are the predominant source of interleukin-17 in affected joints in collagen- 143,152 their ability to traffic to local sites of infection. Moreover, the induced arthritis, but not in rheumatoid arthritis. Arthritis Rheum 2009; 60: 2294– APC function of cd-T cells further favors their application in inducing 2303. 12 Lalor SJ, Dungan LS, Sutton CE, Basdeo SA, Fletcher JM, Mill KH. Caspase-1- antigen-specific immune responses to efficiently eliminate patho- processed cytokines IL-1b and IL-18 promote IL-17 production by cd and CD4 T gens.153 Finally, over 40 years of usage in the clinic cells that mediate . J Immunol 2011; 186: 5738–5748. offers abundant references for their use in expanding and activating 13 Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH et al. Interleukin- 1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying cd-T cells in vivo, although attention must still be paid to the mild or Th17 responses and autoimmunity. Immunity 2009; 31: 331–341. moderate acute responses evoked by their injection.154,155 14 Fink DR, Holm D, Schlosser A, Nielsen O, Latta M, Lozano F et al. Elevated numbers of SCART11 gammadelta T cells in skin inflammation and inflammatory bowel disease. The major concern with using cd-T cell-based anti-infection ther- Mol Immunol 2010; 47: 1710–1718. apy comes from its pro-inflammatory characteristics. These potential 15 Smith E, Prasad KM, Butcher M, Dobrian A, Kolls JK, Ley K et al. Blockade of risks might be induced by overdoses or bystander effects and result in interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient 13 mice. Circulation 2010; 121: 1746–1755. cd-T cell-triggered autoimmune diseases or general inflammatory 16 Murdoch JR, Lloyd CM. Resolution of allergic airway inflammation and airway 156 diseases. It has been shown that one auto-aggressive cd-T-cell sub- hyperreactivity is mediated by IL-17 producing cdT cells. Am J Respir Crit Care Med set recognizing aminoacyl-tRNA synthetases that are shared by bac- 2010; 182: 464–476. 17 Jin Y, Xia MC, Saylor CM, Narayan K, Kang J, Wiest DL et al. Cutting edge: intrinsic teria and humans can be detected in some myositis patients and might programming of thymic cdT cells for specific peripheral tissue localization. J Immunol contribute to the pathogenesis of their disease.157 Thus, a thorough 2010; 185: 7156–7160. understanding of the migration, differentiation and transformation of 18 Chennupati V, Worbs T, Liu X, Malinarich FH, Schmitz S, Haas JD et al. Intra- and intercompartmental movement of cd T cells: intestinal intraepithelial and peripheral activated cd-T cells under physiological and pathological condi- cd T cells represent exclusive nonoverlapping populations with distinct migration tions158 should be achieved before their clinical application. characteristics. J Immunol 2010; 185: 5160–5168. 19 Eberl M, Engel R, Beck E, Jomaa H. Differentiation of human gamma-delta T cells towards distinct memory phenotypes. Cell Immunol 2002; 218: 1–6. SUMMARY 20 Ribot JC, deBarros A, Pang DJ, Neves JF, Peperzak V, Roberts SJ et al. CD27 is a cd thymic determinant of the balance between interferon-gamma- and - In summary, -T cells play distinct roles in human infectious diseases producing gammadelta T cell subsets. Nat Immunol 2009; 10: 427–436. corresponding to their distribution and subpopulations. The anti-infec- 21 Gioia C, Agrati C, Casetti R, Cairo C, Borsellino G, Battistini L et al. Lack of CD27- tion activities of cd-T cells can be initiated by signals from hosts and CD45RA-V gamma 9V delta 21 T cell effectors in immunocompromised hosts and during active pulmonary tuberculosis. J Immunol 2002; 168: 1484–1489. pathogens and carried out by direct cytotoxicity against infected cells or 22 Qin G, Liu Y, Zheng J, Xiang Z, Ng IH, Malik Peiris JS et al. Phenotypic and functional through cytokine production or by indirect pathways involving mul- characterization of human gammadelta T-cell subsets in response to influenza A tiple immune system components. As a bridge between innate immun- viruses. J Infect Dis 2012; 205: 1646–1653. 23 Poccia F, Agrati C, Martini F, Capobianchi MR, Wallace M, Malkovsky M. Antiviral ity and adaptive immunity, cd-T cells exhibit diverse advantages in reactivities of gammadelta T cells. Microbes Infect 2005; 7: 518–528. anti-infection responses. Although the potential of cd-T cells for treat- 24 Sciammas R, Bluestone JA. TCRgammadelta cells and viruses. Microbes Infect 1999; ing human diseases has been significantly improved with the applica- 1: 203–212. 25 Hoq MM, Suzutani T, Toyoda T, Horiike G, Yoshida I, Azuma M. Role of gamma delta tion of and the advancement of our understanding of TCR1 lymphocytes in the augmented resistance of trehalose 6,69-dimycolate-treated their multifaceted characteristics, the clinical usage of cd-T cell-based mice to influenza virus infection. J Gen Virol 1997; 78(Pt 7): 1597–1603. therapies requires more in vivo evidence from further investigations 26 Qin G, Liu Y, Zheng J, Ng IH, Xiang Z, Lam KT et al. Type 1 responses of human Vgamma9Vdelta2 T cells to influenza A viruses. J Virol 2011; 85: 10109–10116. into their roles under physiological and pathological conditions. 27 Qin G, Herold MJ, Kimmel B, Mu¨ller I, Rincon-Orozco B, Kunzmann V et al. This work was supported in part by the Area of Excellence program Phosphoantigen-expanded human gammadelta T cells display potent cytotoxicity against -derived macrophages infected with human and avian influenza on influenza, which is supported by the University Grants Committee viruses. J Infect Dis 2009; 200: 858–865. of the Hong Kong SAR, China (Project No. AoE/M-12/06), the 28 Tu W, Zheng J, Liu Y, Sia SF, Liu M, Qin G et al. The aminobisphosphonate General Research Fund and the Research Grants Council of Hong pamidronate controls influenza pathogenesis by expanding a gammadelta T cell population in humanized mice. J Exp Med 2011; 208: 1511–1522. Kong (HKU 777108M, HKU777407, HKU768108, HKU781211). 29 Meuter S, Eberl M, Moser B. Prolonged antigen survival and cytosolic export in cross- presenting human cd T cells. Proc Natl Acad Sci USA 2010; 107: 8730–8735. 30 Fang H, Welte T, Zheng X, Chang GJ, Holbrook MR, Soong L et al. gammadelta T cells promote the maturation of dendritic cells during West Nile virus infection. FEMS Immunol Med Microbiol 2010; 59: 71–80. 1 Kaufmann SH. Robert Koch, the Nobel Prize, and the ongoing threat of tuberculosis. 31 Puttur FK, Fernandez MA, White R, Roediger B, Cunningham AL, Weninger W et al. N Engl J Med 2005; 353: 2423–2426. Herpes simplex virus infects skin cd T cells before Langerhans cells and impedes

Cellular & Molecular Immunology cd-T cells in anti-infection immunity J Zheng et al 55

migration of infected langerhans cells by inducing apoptosis and blocking E-cadherin 59 Dieude M, Striegl H, Tyznik AJ, Wang J, Behar SM, Piccirillo CA et al. Cardiolipin binds downregulation. J Immunol 2010; 185: 477–487. to CD1d and stimulates CD1d-restricted cd T cells in the normal murine repertoire. 32 Aoyagi M, Shimojo N, Sekine K, Nishimuta T, Kohno Y. Respiratory syncytial virus J Immunol 2011; 186: 4771–4781. infection suppresses IFN-gamma production of gammadelta T cells. Clin Exp 60 Sarikonda G, Wang H, Puan KJ, Liu XH, Lee HK, Song Y et al. Photoaffinity antigens for Immunol 2003; 131: 312–317. human cd T Cells. J Immunol 2008; 181: 7738–7750. 33 Maccario R, Revello MG, Comoli P, Montagna D, Locatelli F, Gerna G. HLA- 61 Ribot JC, Debarros A, Silva-Santos B. Searching for ‘‘signal 2’’: costimulation unrestricted killing of HSV-1-infected mononuclear cells. Involvement of either requirements of gammadelta T cells. Cell Mol Life Sci 2011; 68: 2345–2355. gamma/delta1 or alpha/beta1 human cytotoxic T lymphocytes. J Immunol 1993; 62 Witherden DA, Havran WL. Molecular aspects of epithelial gammadelta T cell 150: 1437–1445. regulation. Trends Immunol 2011; 32: 265–271. 34 Knight A, Madriga AJ, Grace S, Sivakumaran J, Kottaridis P, Mackinnon S et al. The 63 Budd RC, Russell JQ, van Houten N, Cooper SM, Yagita H, Wolfe J. CD2 expression role of Vdelta2-negative gamma-delta T cells during cytomegalovirus reactivation in correlates with proliferative capacity of alpha beta1 or gamma delta1 CD42CD82 T recipients of allogeneic stem cell transplants. Blood 2010; 116: 2164–2172. cells in lpr mice. J Immunol 1992; 148: 1055–1064. 35 Devaud C, Bilhere E, Loizon S, Pitard V, Behr C, Moreau JF et al. Antitumor activity of 64 Lafont V, Liautard J, Gross A, Liautard JP, Favero J. -alpha cd T cells reactive against cytomegalovirus-infected cells in a mouse xenograft tumor production is differently regulated in gamma delta and alpha beta human T model. Res 2009; 69: 3971–3978. lymphocytes. J Biol Chem 2000; 275: 19282–19287. 36 Vermijlen D, Brouwer M, Donner C, Liesnard C, Tackoen M, van Rysselberge M et al. 65 Penninger JM, Timms E, Shahinian A, Jezo-Bremond A, Nishina H, Ionescu J et al. Human cytomegalovirus elicits fetal cd T cell responses in utero. J Exp Med 2010; Alloreactive gamma delta utilize distinct costimulatory signals from 207: 807–821. peripheral T cells. J Immunol 1995; 155: 3847–3855. 37 Wallace M, Bartz SR, Chang WL, Mackenzie DA, Pauza CD, Malkovsky M. Gamma 66 Shao Z, Schwarz H. CD137 ligand, a member of the tumor necrosis factor family, delta T responses to HIV. Clin Exp Immunol 1996; 103: 177–184. regulates immune responses via reverse signal transduction. J Leuk Biol 2011; 89: 38 Agerberth B, Charo J, Werr J, Olsson B, Idali F, Lindbom L et al. The human 21–29. antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed 67 Caccamo N, Battistini L, Bonneville M, Poccia F, Fournie´ JJ, Meraviglia S et al. CXCR5 by specific lymphocyte and monocyte populations. Blood 2000; 96: 3086–3093. identifies a subset of Vgamma9Vdelta2 T cells which secrete IL-4 and IL-10 and help 39 Poccia F, Gioia C, Martini F, Sacchi A, Piacentini P, Tempestilli M et al. Zoledronic B cells for antibody production. J Immunol 2006; 177: 5290–5295. acid and interleukin-2 treatment improves immunocompetence in HIV-infected 68 Witherden DA, Verdino P, Rieder SE, Garijo O, Mills RE, Teyton L et al. The junctional persons by activating Vgamma9Vdelta2 T cells. AIDS 2009; 23: 555–565. adhesion molecule JAML is a costimulatory receptor for epithelial gammadelta T cell 40 de Paoli P, Gennari D, Martelli P, Cavarzerani V, Comoretto R, Santini G. Gamma delta activation. Science 2010; 329: 1205–1210. T cell receptor-bearing lymphocytes during Epstein–Barr virus infection. J Infect Dis 69 Ciucci A, Gabriele I, Percario ZA, Affabris E, Colizzi V, Mancino G. HMGB1 and cord 1990; 161: 1013–1016. blood: its role as immuno-adjuvant factor in innate immunity. PloS ONE 2011; 6: 41 Tseng CT, Miskovsky E, Houghton M, Klimpel GR. Characterization of liver T-cell e23766. receptor gammadelta T cells obtained from individuals chronically infected with 70 Uchida Y, Kawai K, Ibusuki A, Kanekura T. Role for E-cadherin as an inhibitory hepatitis C virus (HCV): evidence for these T cells playing a role in the liver receptor on epidermal cd T cells. J Immunol 2011; 186: 6945–6954. pathology associated with HCV infections. Hepatology 2001; 33: 1312–1320. 71 Das H, Groh V, Kuijl C, Sugita M, Morita CT, Spies T et al. MICA engagement by human 42 Landmeier S, Altvater B, Pscherer S, Juergens H, Varnholt L, Hansmeier A et al. Vgamma2Vdelta2 T cells enhances their antigen-dependent effector function. Activated human gammadelta T cells as stimulators of specific CD81 T-cell Immunity 2001; 15: 83–93. responses to subdominant Epstein Barr virus epitopes: potential for 72 Rincon-Orozco B, Kunzmann V, Wrobel P, Kabelitz D, Steinle A, Herrmann T. of cancer. J Immunother 2009; 32: 310–321. Activation of V gamma 9V delta 2 T cells by NKG2D. J Immunol 2005; 175: 2144– 43 Mishra R, Chen AT, Welsh RM, Szomolanyi-Tsuda E. NK cells and gammadelta T cells 2151. mediate resistance to polyomavirus-induced tumors. PLoS Pathog 2010; 6: 73 Angelini DF, Micucci F, Poccia F, Semenzato G, Borsellino G, Santoni A et al. NKG2A e1000924. inhibits NKG2C effector functions of cd T cells: implications in health and disease. 44 Chen ZW, Letvin NL. Vgamma2Vdelta21 T cells and anti-microbial immune J Leukoc Biol 2010; 89: 75–84. responses. Microbes Infect 2003; 5: 491–498. 74 Wesch D, Peters C, Oberg HH, Pietschmann K, Kabelitz D. Modulation of gammadelta 45 O’Brien RL, Roark CL, Born WK. IL-17-producing gammadelta T cells. Eur J Immunol T cell responses by TLR ligands. Cell Mol Life Sci 2011; 68: 2357–2370. 2009; 39: 662–666. 75 Devilder MC, Allain S, Dousset C, Bonneville M, Scotet E. Early triggering of exclusive 46 Wang L, Kamath A, Das H, Li L, Bukowski JF. Antibacterial effect of human V gamma IFN-gamma responses of human Vgamma9Vdelta2 T cells by TLR-activated myeloid 2V delta 2 T cells in vivo. J Clin Invest 2001; 108: 1349–1357. and plasmacytoid dendritic cells. J Immunol 2009; 183: 3625–3633. 47 Kabelitz D, Bender A, Schondelmaier S, Schoel B, Kaufmann SH. A large fraction of 76 Pietschmann K, Beetz S, Welte S, Martens I, Gruen J, Oberg HH et al. Toll-like receptor human peripheral blood gamma/delta1 T cells is activated by Mycobacterium expression and function in subsets of human gammadelta T lymphocytes. Scand J tuberculosis but not by its 65-kD . J Exp Med 1990; 171: 667–679. Immunol 2009; 70: 245–255. 48 Chen ZW. Immunology of AIDS virus and mycobacterial co-infection. Curr HIV Res 77 Oberg HH, Ly TT, Ussat S, Meyer T, Kabelitz D, Wesch D. Differential but direct 2004; 2: 351–355. abolishment of human suppressive capacity by various TLR2 49 Xu S, Han Y, Xu X, Bao Y, Zhang M, Cao X et al. IL-17A-producing cdT cells promote ligands. J Immunol 2010; 184: 4733–4740. CTL responses against Listeria monocytogenes infection by enhancing 78 Wesch D, Beetz S, Oberg HH, Marget M, Krengel K, Kabelitz D. Direct costimulatory cross-presentation. J Immunol 2010; 185: 5879–5887. effect of TLR3 ligand poly(I:C) on human gamma delta T lymphocytes. J Immunol 50 Egan CE, Dalton JE, Andrew EM, Smith JE, Gubbels MJ, Striepen B et al.A 2006; 176: 1348–1354. requirement for the Vgamma11 subset of peripheral gammadelta T cells in the 79 Rothenfusser S, Hornung V, Krug A, Towarowski A, Krieg AM, Endres S et al. Distinct control of the systemic growth of Toxoplasma gondii and infection-induced CpG oligonucleotide sequences activate human gamma delta T cells via interferon- pathology. J Immunol 2005; 175: 8191–8199. alpha/-beta. Eur J Immunol 2001; 31: 3525–3534. 51 Horowitz A, Newman KC, Evans JH, Korbel DS, Davis DM, Riley EM et al. Cross-talk 80 Born WK, Zhang L, Nakayama M, Jin N, Chain JL, Huang Y et al. antigens for between T cells and NK cells generates rapid effector responses to Plasmodium gamma/delta T cells. Cell Mol Life Sci 2011; 68: 2335–2343. falciparum-infected erythrocytes. J Immunol 2010; 184: 6043–6052. 81 Fu YX, Cranfill R, Vollmer M, van der Zee R, O’Brien RL, Born W. In vivo response of 52 Weidanz WP, LaFleur G, Brown A, Burns JM Jr, Gramaglia I, van der Heyde HC. cdT murine gamma delta T cells to a heat shock protein-derived peptide. Proc Natl Acad cells but not NK cells are essential for cell-mediated immunity against Plasmodium Sci USA 1993; 90: 322–326. chabaudi malaria. Infect Immun 2010; 78: 4331–4340. 82 Mohan JF, Levisetti MG, Calderon B, Herzog JW, Petzold SJ, Unanue ER et al. Unique 53 Chen ZW. Immune biology of Ag-specific gammadelta T cells in infections. Cell Mol autoreactive T cells recognize peptides generated within the islets of Life Sci 2011; 68: 2409–2417. Langerhans in autoimmune diabetes. Nat Immunol 2010; 11: 350–354. 54 Morita CT, Mariuzza RA, Brenner MB. Antigen recognition by human gamma delta T 83 Kozbor D, Trinchieri G, Monos DS, Isobe M, Russo G, Haney JA et al. Human TCR- cells: pattern recognition by the adaptive immune system. Springer Semin gamma1/delta1, CD81 T lymphocytes recognize tetanus toxoid in an MHC-restricted Immunopathol 2000; 22: 191–217. fashion. J Exp Med 1989; 169: 1847–1851. 55 Chargui J, Combaret V, Scaglione V, Iacono I, Pe´ri V, Valteau-Couanet D et al. 84 Johnson RM, Lancki DW, Sperling AI, Dick RF, Spear PG, Fitch FW et al. A murine Bromohydrin pyrophosphate-stimulated Vgamma9delta2 T cells expanded ex vivo CD42, CD82 T cell receptor-gamma delta T lymphocyte clone specific for herpes from patients with poor-prognosis neuroblastoma lyse autologous primary tumor simplex virus glycoprotein I. J Immunol 1992; 148: 983–988. cells. J Immunother 2010; 33: 591–598. 85 O’Brien RL, Happ MP, Dallas A, Palmer E, Kubo R, Born WK. Stimulation of a major 56 Morita CT, Beckman EM, Bukowski JF, Tanaka Y, Band H, Bloom BR et al. Direct subset of lymphocytes expressing T cell receptor gamma delta by an antigen derived presentation of nonpeptide prenyl pyrophosphate antigens to human gamma delta T from Mycobacterium tuberculosis. Cell 1989; 57: 667–674. cells. Immunity 1995; 3: 495–507. 86 Happ MP, Kubo RT, Palmer E, Born WK, O’Brien RL. Limited receptor repertoire in a 57 Wei H, Huang D, Lai X, Chen M, Zhong W, Wang R et al. Definition of APC presentation of mycobacteria-reactive subset of gamma delta T lymphocytes. Nature 1989; 342: phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate to Vgamma2Vdelta 2 696–698. TCR. JImmunol2008; 181: 4798–4806. 87 Rust CJ, Verreck F, Vietor H, Koning F. Specific recognition of staphylococcal 58 Agea E, Russano A, Bistoni O, Mannucci R, Nicoletti I, Corazzi L et al. Human CD1- enterotoxin A by human T cells bearing receptors with the V gamma 9 region. restricted T cell recognition of from pollens. J Exp Med 2005; 202: 295–308. Nature 1990; 346: 572–574.

Cellular & Molecular Immunology cd-T cells in anti-infection immunity J Zheng et al 56

88 Guo Y, Ziegler HK, Safley SA, Niesel DW, Vaidya S, Klimpel GR. Human T-cell 119 Kang N, Tang L, Li X, Wu D, Li W, Chen X et al. Identification and characterization of recognition of Listeria monocytogenes: recognition of listeriolysin O by TcR alpha Foxp31 gammadelta T cells in mouse and human. Immunol Lett 2009; 125: 105– beta1 and TcR gamma delta1 T cells. Infect Immun 1995; 63: 2288–2294. 113. 89 Holoshitz J, Koning F, Coligan JE, de Bruyn J, Strober S. Isolation of CD42 CD82 120 Li X, Kang N, Zhang X, Dong X, Wei W, Cui L et al. Generation of human regulatory cd T mycobacteria-reactive T lymphocyte clones from rheumatoid arthritis synovial fluid. cells by TCRcd stimulation in the presence of TGF-b and their involvement in the Nature 1989; 339: 226–229. pathogenesis of systemic lupus erythematosus. J Immunol 2011; 186: 6693–6700. 90 Shen Y, Zhou D, Qiu L, Lai X, Simon M, Shen L et al. Adaptive immune response of 121 Berkun, Y. Bendersky A, Gerstein M, Goldstein I, Padeh S, Bank I. cdT cells in juvenile Vgamma2Vdelta21 T cells during mycobacterial infections. Science 2002; 295: idiopathic arthritis: higher percentages of synovial Vd11 and Vc91 T cell subsets are 2255–2258. associated with milder disease. J Rheumatol 2011; 38: 1123–1129. 91 Bonneville M, O’Brien RL, Born WK. Gammadelta T cell effector functions: a blend of 122 Yurchenko E, Levings MK, Piccirillo CA. CD41 Foxp31 regulatory T cells suppress innate programming and acquired plasticity. Nat Rev Immunol 2010; 10: 467–478. gammadelta T-cell effector functions in a model of T-cell-induced mucosal 92 Born WK, O’Brien RL. Antigen-restricted gammadelta T-cell receptors? Arch Immunol inflammation. Eur J Immunol 2011; 41: 3455–3466. Ther Exp (Warsz) 2009; 57: 129–135. 123 Park SG, Mathur R, Long M, Hosh N, Hao L, Hayden MS et al. T regulatory cells 93 Paget C, Chow MT, Duret H, Mattarollo SR, Smyth MJ. Role of gammadelta T cells in maintain intestinal homeostasis by suppressing gammadelta T cells. Immunity alpha-galactosylceramide-mediated immunity. JImmunology2012; 188: 3928– 2010; 33: 791–803. 3939. 124 Do JS, Visperas A, O’Brien RL, Min B. CD4 T cells play important roles in maintaining 94 de Koning PJ, Kummer JA, de Poot SA, Quadir R, Broekhuizen R, McGettrick AF et al. IL-17-producing gammadelta T-cell subsets in naive animals. Immunol Cell Biol The cytotoxic protease granzyme M is expressed by lymphocytes of both the innate and 2011; 90: 396–403. adaptive immune system. Mol Immunol 2009; 47: 903–911. 125 Miko E, Szereday L, Barakonyi A, Jarkovich A, Varga P, Szekeres-Bartho J et al. 1 95 Couzi L, Pitard V, Sicard X, Garrigue I, Hawchar O, Merville P et al. Antibody- Immunoactivation in preeclampsia: Vdelta2 and regulatory T cells during the dependent anti-cytomegalovirus activity of human gammadelta T cells expressing inflammatory stage of disease. J Reprod Immunol 2009; 80: 100–108. CD16 (FcgammaRIIIa). Blood 2012; 119: 1418–1427. 126 Boyman O, Krieg C, Homann D, Sprent J. Homeostatic maintenance of T cells and 96 McAleer JP, Kolls JK. Mechanisms controlling Th17 cytokine expression and host natural killer cells. Cell Mol Life Sci 2012; 69: 1597–1608. defense. J Leuk Biol 2011; 90: 263–270. 127 Meraviglia S, Caccamo N, Salerno A, Sireci G, Dieli F. Partial and ineffective activation 97 Li Z, Burns AR, Byeseda Miller S, Smith CW. CCL20, cd T cells, and IL-22 in corneal of V gamma 9V delta 2 T cells by Mycobacterium tuberculosis-infected dendritic cells. epithelial healing. FASEB J 2011; 25: 2659–2668. J Immunol 2010; 185: 1770–1776. 98 Zenewicz LA, Flavell RA. Recent advances in IL-22 biology. Int Immunol 2011; 23: 128 Meeks KD, Sieve AN, Kolls JK, Ghilardi N, Berg RE. IL-23 is required for protection 159–163. against systemic infection with Listeria monocytogenes. JImmunol2009; 183: 99 Prinz I. Dynamics of the interaction of gammadelta T cells with their neighbors in vivo. 8026–8034. Cell Mol Life Sci 2011; 68: 2391–2398. 129 Laky K, Sieve AN, Kolls JK, Ghilardi N, Berg RE. Enterocyte expression of interleukin 7 100 Wands JM, Roark CL, Aydintug MK, Jin N, Hahn YS, Cook L et al. Distribution and induces development of gammadelta T cells and Peyer’s patches. J Exp Med 2000; leukocyte contacts of gammadelta T cells in the lung. J Leuk Biol 2005; 78: 1086– 191: 1569–1580. 1096. 130 Thedrez A, Harly C, Morice A, Salot S, Bonneville M, Scotet E. IL-21-mediated 101 Gazit R, Gruda R, Elboim M, Arnon TI, Katz G, Achdout H et al. Lethal influenza potentiation of antitumor cytolytic and proinflammatory responses of human infection in the absence of the receptor gene Ncr1. Nat Immunol Vc9Vd2 T cells for adoptive immunotherapy. J Immunol 2009; 182: 3423–3431. 2006; 7: 517–523. 131 Dungan LS, Mills KH. Caspase-1-processed IL-1 family cytokines play a vital role in driving innate IL-17. Cytokine 2011; 15: 126–132. 102 Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing 132 Gong G, Shao L, Wang Y, Chen CY, Huang D, Yao S et al. Phosphoantigen-activated V gammadelta T cells selectively expand in response to pathogen products and 1 1 1 environmental signals. Immunity 2009; 31: 321–330. gamma 2V delta 2 T cells antagonize IL-2-induced CD4 CD25 Foxp3 T regulatory cells in mycobacterial infection. Blood 2009; 113: 837–845. 103 Silva-Santos B, Pennington DJ, Hayday AC. Lymphotoxin-mediated regulation of 133 Henry T, Kirimanjeswara GS, Ruby T, Jones JW, Peng K, Perret M et al. Type I IFN gammadelta cell differentiation by alphabeta T cell progenitors. Science 2005; signaling constrains IL-17A/F secretion by cd T cells during bacterial infections. 307: 925–928. J Immunol 2010; 184: 3755–3767. 104 Pennington DJ, Silva-Santos B, Shires J, Theodoridis E, Pollitt C, Wise EL et al. The 134 Rojas RE, Balaji KN, Subramanian A, Boom WH. Regulation of human CD41 inter-relatedness and interdependence of mouse T cell receptor gammadelta1 and alphabeta T-cell-receptor-positive (TCR1) and gammadelta TCR1 T-cell responses alphabeta1 cells. Nat Immunol 2003; 4: 991–998. to Mycobacterium tuberculosis by interleukin-10 and transforming growth factor 105 Rojas RE, Torres M, Fournie JJ, Harding CV, Boom WH. Phosphoantigen presentation beta. Infect Immun 1999; 67: 6461–6472. by macrophages to Mycobacterium tuberculosis-reactive Vgamma9Vdelta21 T cells: 135 Pechhold K, Wesch D, Schondelmaier S, Kabelitz D. Primary activation of V gamma 9- modulation by chloroquine. Infect Immun 2002; 70: 4019–4027. expressing gamma delta T cells by Mycobacterium tuberculosis. Requirement for Th1- 106 Moser B, Eberl M. gammadelta T-APCs: a novel tool for immunotherapy? Cell Mol Life type CD4 T cell help and inhibition by IL-10. J Immunol 1994; 152: 4984–4992. Sci 2011; 68: 2443–2452. 136 Dieli F, Poccia F, Lipp M, Sireci G, Caccamo N, Di Sano C et al. Differentiation of 107 Brandes M, Willimann K, Bioley G, Le´vy N, Eberl M, Luo M et al. Cross-presenting effector/memory Vdelta2 T cells and migratory routes in lymph nodes or inflammatory human gammadelta T cells induce robust CD81 alphabeta T cell responses. Proc Natl sites. J Exp Med 2003; 198: 391–397. Acad Sci USA 2009; 106: 2307–2312. 137 Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M et al. Generation of 108 Maniar A, Zhang X, Lin W, Gastman BR, Pauza CD, Strome SE et al. Human cd T functional human T-cell subsets with HLA-restricted immune responses in HLA lymphocytes induce robust NK cell mediated antitumor cytotoxicity through CD137 class I expressing NOD/SCID/IL2rcnull humanized mice. Proc Natl Acad Sci USA engagement. Blood 2010; 116: 1726–1733. 2010; 107: 13022–13027. 109 Nussbaumer O, Gruenbacher G, Gander H, Thurnher M. DC-like cell-dependent 138 Sato K, Kondo M, Sakuta K, Hosoi A, Noji S, Sugiura M et al. Impact of culture medium activation of human natural killer cells by the bisphosphonate is on the expansion of T cells for immunotherapy. Cytotherapy 2009; 11: 936–946. regulated by T lymphocytes. Blood 2011; 118: 2743–2751. cd 139 Bennouna J, Bompas E, Neidhardt EM, Rolland F, Philip I, Gale´aCet al. Phase-I study 110 Cheng L, Cui Y, Shao H, Han G, Zhu L, Huang Y et al. Mouse gammadelta T cells are of Innacell gammadelta, an autologous cell-therapy product highly enriched in capable of expressing MHC class II molecules, and of functioning as antigen- gamma9delta2 T lymphocytes, in combination with IL-2, in patients with presenting cells. J Neuroimmunol 2008; 203: 3–11. metastatic . Cancer Immunol Immunother 2008; 57: 1599– 111 Kabelitz D. gammadelta T-cells: cross-talk between innate and adaptive immunity. 1609. Cell Mol Life Sci 2011; 68: 2331–2333. 140 Kobayashi H, Tanaka Y, Yagi J, Osaka Y, Nakazawa H, Uchiyama T et al. Safety profile 112 Eberl, M. Roberts GW, Meuter S, Williams JD, Topley N, Moser B. A rapid crosstalk of and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against human gammadelta T cells and monocytes drives the acute inflammation in bacterial advanced renal cell carcinoma: a pilot study. Cancer Immunol Immunother 2007; 56: infections. PLoS Pathog 2009; 5: e1000308. 469–476. 113 Huber SA. gammadelta T lymphocytes kill T regulatory cells through CD1d. 141 Nakajima J, Murakawa T, Fukami T, Goto S, Kaneko T, Yoshida Y et al. A phase I study Immunology 2010; 131: 202–209. of adoptive immunotherapy for recurrent non-small-cell patients with 114 Liu W, Huber SA. Cross-talk between CD1d-restricted NKT cells and gammadelta cells autologous gammadelta T cells. Eur J Cardiothorac Surg 2010; 37: 1191–1197. in t regulatory cell response. Virol J 2011; 8: 32. 142 Kobayashi H, Tanaka Y, Shimmura H, Minato N, Tanabe K. Complete remission of lung 115 Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B et al. CXC following adoptive immunotherapy using activated autologous cd T-cells in receptor 5 expression defines follicular homing T cells with helper function. a patient with renal cell carcinoma. Anticancer Res 2010; 30: 575–579. J Exp Med 2000; 192: 1553–1562. 143 Ali Z, Shao L, Halliday L, Reichenberg A, Hintz M, Jomaa H et al. Prolonged (E)-4- 116 Vinuesa CG, Tangye SG, Moser B, Mackay CR. Follicular B helper T cells in antibody hydroxy-3-methyl-but-2-enyl pyrophosphate-driven antimicrobial and cytotoxic responses and autoimmunity. Nat Rev Immunol 2005; 5: 853–865. responses of pulmonary and systemic Vgamma2Vdelta2 T cells in macaques. 117 Do JS, Min B. IL-15 produced and trans-presented by DCs underlies homeostatic J Immunol 2007; 179: 8287–8296. competition between CD8 and cd T cells in vivo. Blood 2009; 113: 6361–6371. 144 Huang D, Chen CY, Ali Z, Shao L, Shen L, Lockman HA et al. Antigen-specific 118 Kuhl AA, Pawlowski NN, Grollich K, Blessenohl M, Westermann J, Zeitz M et al. Vgamma2Vdelta2 T effector cells confer homeostatic protection against pneumonic Human peripheral gammadelta T cells possess regulatory potential. Immunology plaque lesions. Proc Natl Acad Sci USA 2009; 106: 7553–7558. 2009; 128: 580–588. 145 Russell RG. Bisphosphonates: the first 40 years. 2011; 49: 2–19.

Cellular & Molecular Immunology cd-T cells in anti-infection immunity J Zheng et al 57

146 Castella B, Riganti C, Fiore F, Pantaleoni F, Canepari ME, Peola S et al. Immune nonlymphoid tissues in Mycobacterium tuberculosis infection. Infect Immun 2008; modulation by zoledronic acid in human myeloma: an advantageous cross talk 76: 426–436. between Vc9Vd2 T cells, cd CD81 T cells, regulatory T cells, and dendritic cells. 153 Altvater B, Pscherer S, Landmeier S, Kailayangiri S, Savoldo B, Juergens H et al. J Immunol 2011; 187: 1578–1590. Activated human gammadelta T cells induce peptide-specific CD81 T-cell 147 Kabelitz D, Wesch D, He W. Perspectives of gammadelta T cells in tumor immunology. responses to tumor-associated self-antigens. Cancer Immunol Immunother 2011; Cancer Res 2007; 67: 5–8. 61: 385–396. 148 Laggner U, Lopez JS, Perera G, Warbey VS, Sita-Lumsden A, O’Doherty MJ et al. 154 Dieli F, Gebbia N, Poccia F, Caccamo N, Montesano C, Fulfaro F et al. Induction of Regression of melanoma metastases following treatment with the n-bisphosphonate gammadelta T-lymphocyte effector functions by bisphosphonate zoledronic acid in zoledronate and localised radiotherapy. Clin Immunol 2009; 131: 367–373. cancer patients in vivo. Blood 2003; 102: 2310–2311. 149 Mehrle S, Watzl C, von Lilienfeld-Toal M, Amoroso A, Schmidt J, Ma¨rten A. 155 Kunzmann V, Bauer E, Wilhelm M. Gamma/delta T-cell stimulation by pamidronate. N Comparison of phenotype of gammadelta T cells generated using various cultivation Engl J Med 1999; 340: 737–738. methods. Immunol Lett 2009; 125: 53–58. 156 Lukens JR, Barr MJ, Chaplin DD, Chi H, Kanneganti TD. Inflammasome-derived IL- 150 Salot S, Bercegeay S, Dreno B, Sa¨ıagh S, Scaglione V, Bonnafous C et al. Large scale 1beta regulates the production of GM-CSF by CD41 T cells and gammadelta T cells. expansion of Vgamma9Vdelta 2 T lymphocytes from human peripheral blood J Immunol 2012; 188: 3107–3115. mononuclear cells after a positive selection using MACS ‘‘TCR Gamma/Delta1 T 157 Bruder J, Siewert K, Obermeier B, Malotka J, Scheinert P, Kellermann J et al. Target Cell Isolation Kit’’. J Immunol Methods 2009; 347: 12–18. specificity of an autoreactive human gammadelta-T cell receptor in myositis. J Biol 151 Zhou J, Kang N, Cui L, Ba D, He W. Anti-gammadelta TCR antibody-expanded Chem 2012; 287: 20986–20995. gammadelta T cells: a better choice for the adoptive immunotherapy of lymphoid 158 Placido R, Auricchio G, Gabriele I, Galli E, Brunetti E, Colizzi V et al. Characterization malignancies. Cell Mol Immunol 2011; 9: 34–44. of the immune response of human cord-blood derived gamma/delta T cells to 152 Huang D, Shen Y, Qiu L, Chen C, Shen L, Estep J et al. Immune distribution and stimulation with aminobisphosphonate compounds. Int J Immunopathol Pharmacol localization of phosphoantigen-specific Vgamma2Vdelta2 T cells in lymphoid and 2011; 24: 101–110.

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