Highlights of the Advances in Basic Immunology in 2011

REVIEW

Highlights of the advances in basic immunology in 2011

Juan Liu1, Shuxun Liu1 and Xuetao Cao1,2

In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells (ILCs). Helper T cells and regulatory T (Treg) cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs (miRNAs) in T cell immunity are discussed, as is the recent identification of a novel T-cell subset referred to as follicular regulatory T (TFR) cells. Cellular & Molecular Immunology (2012) 9, 197–207; doi:10.1038/cmi.2012.12; published online 23 April 2012

Keywords: ILC; innate immunity; Th17 cells; TFR cells; TLR

INTRODUCTION encountered antigens. T cells, because they control both the establish- The immune system, a collection of tissues, cells and molecules, has ment and regulation of adaptive immunity, have attracted special atten- evolved to recognize and eliminate invading pathogens. Broadly, the tion in recent decades. Whereas Th1 and Th2 were first described in the immune system can be divided into two categories, the innate 1980s, interest in several other T helper subsets, including regulatory T immune system and the adaptive immune system. Although it has (Treg) cells, Th17 cells, follicular T helper (TFH) cells and regulatory been known for many years that the innate immune system constitu- follicular T (TFR) cells, has emerged in the last decade because of their tes the first line of defense against pathogens, how the innate immune unique cytokine profiles, functions and disease associations.3 In com- system senses danger signals from invading pathogens and distin- parison with T cells, the function of B cells and their flexibility and guishes self from non-self was not understood until the identification elasticity in development remain more mysterious, and the further of pattern-recognition receptors (PRRs). PRRs, which are expressed investigation of these cells has the potential for fascinating discoveries. on a variety of different cell types, recognize a number of conserved In this review, we look back on the advances in basic immunological structures in pathogens, termed pathogen-associated molecular pat- research that have had the greatest impact in 2011. We include new terns (PAMPs), and activate the downstream intracellular signaling findings on pattern-recognition (special emphasis is placed on nucleic pathways that mount inflammatory responses against invading patho- acid recognition and the regulation of innate immune responses); ILC; gens at the early phase of infection.1 During the course of PRR- the developmental programs of T helper subsets including Th2, Th17, triggered innate immune responses, a number of endogenous molecules Treg, TFH and TFR cells; and T-cell homeostasis (the balance among present in normal individuals exert dialectical regulatory effects on naive, effector and memory T cells). Perspectives and the implications controlling the magnitude and duration of the inflammatory responses of these recent findings for health and diseases, with special emphasis on to avoid harmful immunopathogenesis.2 Recently, in addition to poly- their indications for possible therapeutic strategies, are discussed. morphic nuclear leukocytes, antigen-presenting cells (including dendritic cells (DCs), monocytes and macrophages) and conventional NUCLEIC ACID RECOGNITION natural killer (NK) cells, as well as novel cell subsets such as innate The recognition of the enormous diversity of potential invading patho- lymphoid cells (ILCs), have been identified as members of the innate gens by the innate immune system relies on the ability of the PRRs immune system. The adaptive immune response develops in high-class expressed on innate immune cells to detect the evolutionarily conserved vertebrates in the late phase of infection to eliminate pathogens that structures on microbes, termed PAMPs. The PAMP engagement of have evaded innate immunity. Adaptive immunity is characterized by PRRs causes the activation of a series of downstream signaling events the specificity of antigen recognition mediated by a broad repertoire of that ultimately leads to the expression of pro-inflammatory cytokines antigen-specific receptors and the memory responses to previously and interferons (IFNs), which together orchestrate the early innate 1National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China and 2National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, China Correspondence: Dr J Liu, National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China E-mail: [email protected] or Dr XT Cao, National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China E-mail: [email protected] Received 10 March 2012; accepted 20 March 2012 Highlights of the advances in basic immunology in 2011 J Liu et al 198

immune response and initiate the subsequent activation and shaping of to IFN-a/b and proinflammatory cytokine production in response to adaptive immunity.4 To date, three families of PRRs, including Toll-like pathogenic RNA. receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors In addition to the identification of additional RNA sensors, (RLRs) and nucleotide-binding oligomerization domain (NOD)-like investigators also focused on the molecular mechanisms of RNA receptors (NLRs), have been identified for their indispensable role in sensing and the discrimination between host- and pathogen-derived pathogen recognition and triggering of the antipathogen immune res- RNA. RIG-I is a key innate immune PRR that initiates an antiviral ponse. Nucleic acids are recognized as the essential components of immune response upon detection of the viral RNA PAMPs. viruses that are detected by innate immune receptors.5 However, Recently, Luo et al.,16 Kowalinski et al.17 and Jiang et al.18 inde- because nucleic acids are commonly shared by the pathogen and host, pendently clarified the molecular basis for RIG-I activation by RNA the potential recognition of self nucleic acids by PRRs increases the risk by revealing the conformational switch between the inactivated and of autoimmune or auto-inflammatory diseases. Thus, the specific and activated state of RIG-I. Their work provides an insightful under- effective detection of microbial RNA and DNA is critical for an appro- standing of the molecular mechanism involved in the activation of priate innate immune response against a pathogen. RIG-I by pathogenic RNAs. Furthermore, Daffis et al.19 and Zu¨st Several transmembrane and cytosolic receptors have been identified et al.20 recently identified the critical role of ribose 29-O-methyla- for their ability to recognize multiple forms of RNA and DNA, includ- tion in the mechanism for discriminating between self and non-self ing members of the TLRs, RLRs and several DNA sensors. To date, mRNAs. The 59 cap structures of higher eukaryote mRNAs and four TLR family members, TLR3, TLR7, TLR8 and TLR9, which are many viral RNAs contain ribose 29-O-methylation; however, until localized within endolysosomal compartments, have been studied these reports, the biological role of 29-O-methylation was extensively for their role in nucleic acid recognition and type I IFN unknown. The studies demonstrated that 29-O-methylation of the induction.6 59 cap of viral RNA enabled several viruses to evade innate antiviral Because many viruses complete their entire infectious cycle in the responses in the host, which was attributed to the reduced sensitiv- cytosol, much attention has focused on discovering a mechanism ity to the antiviral effects exhibited by IFIT1 and the inhibition of for the detection of cytosolic viral RNA and DNA, which includes type I IFN induction mediated by the cytosolic RNA sensor MDA5. the identification of cytosolic PRRs, including the known RIG-I- Therefore, the studies indicate that the 29-O-methylation of cellular like receptors that recognize cytosolic RNA and an analogous family mRNAs is a molecular signature for the discrimination of self and of cytosolic DNA sensors. The recognition of nucleic acids by cyto- non-self mRNAs.21 solic PRRs activates the transcription factor IRF3 or IRF7 (IFN regulatory factor 3 or 7) signaling pathways and potently induces Recognition of cytosolic DNA the production of type I IFN. In some cases, cytosolic DNA recog- Regarding the recognition of microbial DNA, investigators previously nition also favors the activation of an inflammasome for the pro- identified DAI (DNA-dependent activator of IFN-regulatory fac- duction of IL-1b. A number of the latest discoveries pertaining to tors),22 AIM2 (absent in melanoma 2)23–25 and Pol III (DNA-depend- the mechanisms of recognition of cytosolic RNA or DNA by PRRs ent RNA polymerase III)26,27 as major cytosolic DNA sensors. The are discussed below. recognition of cytosolic DNA by DAI triggers the production of type I IFN, similar to that triggered by cytosolic RNA sensing, whereas Recognition of cytosolic RNA recognition by AIM2 activates multiple complexes, termed inflamma- RIG-I7 and MDA5 (melanoma differentiation-associated protein 5),8 somes, which results in the processing and secretion of IL-1b. Pol III both RLR family members, as well as NOD2,9 have been implicated (DNA-dependent RNA polymerase III) recognizes and transcribes in cytosolic RNA sensing. Pichlmair et al.10 reported that the IFN- transfected poly (dA:dT) DNA to 59-ppp dsRNA, which subsequently induced gene product IFIT1 (IFN-induced protein with tetratricopep- activates the RIG-I-dependent signaling pathway.28 Recently, several tide repeats 1) is a sensor for 59-triphosphorylated RNAs of viral origin. additional DNA sensors have been proposed. Unterholzner et al.29 The 59-triphosphate group is a molecular signature within RNA that is identified IFI16 as an intracellular DNA sensor and showed that responsible for its recognition by RIG-I.11,12 Using an affinity proteo- IFI16 (gamma-IFN-inducible protein 16) directly associates with viral mics approach, the authors determined that the antiviral protein IFIT1 DNA motifs and induces IRF3 and NF-kB activation through recruit- binds PPP-RNA with nanomolar affinity. IFIT1, together with other ing the adaptor STING (stimulator of IFN genes), which ultimately IFIT family members, forms a larger protein complex that sequesters mediates the production of IFN-b. IFI16 and AIM2 are PYHIN (Pyrin specific viral nucleic acids in the cytoplasm, which contributes to the and HIN domain-containing protein 1) proteins, which implicates a inhibition of the growth and pathogenicity of viruses containing PPP- central role for PYHIN proteins in DNA sensing. A newly defined RNA.13 In studies by Zhang et al., the DDX1–DDX21–DHX36 com- cytosolic DNA sensor, DDX41, was reported by Zhang et al.30 The plex14 and DHX915 were identified as cytosolic sensors for dsRNA in study showed that DDX41 binds both DNA and STING in the cytosol myeloid DCs. Through the isolation and sequencing of poly I:C-bind- and induces NF-kB and IRF3 activation, leading to type I IFN and ing proteins, the authors showed that the RNA helicases DDX1, cytokine production. Using a pull-down assay, Zhang et al.31 demon- DDX21 and DHX36 form a complex with the TRIF [TIR (Toll-inter- strated that Ku70 is another novel DNA sensor that induces IFN-l1 leukin 1 receptor) domain-containing adaptor protein inducing inter- production through the activation of IRF-1 and IRF-7.32 In addition, feron b] adaptor molecule to sense dsRNA in the cytosol and induce LRRFIP1 (leucine-rich repeat flightless-interacting protein 1), prev- type I IFN and cytokine responses to poly I:C, influenza A virus, and iously identified by our lab, binds exogenous nucleic acids and reovirus in myeloid DCs. In addition, DHX9, a DExDc helicase family increases the expression of IFN-b induced by both dsRNA and member, is another viral RNA sensor in myeloid DCs that specifically dsDNA. LRRFIP1 interacts with and promotes the activation of b- binds the dsRNA motif of poly I:C. DHX9 interacts with IPS-1 (IFN-b catenin, which increases IFN-b expression by binding to IRF3 and promoter stimulator 1, also known as MAVS/VISA/Cardif) to activate recruiting the acetyltransferase p300 to the IFN-b enhanceosome via NF-kB (nuclear factor kappa B) and IRF3 pathways, ultimately leading IRF3.33

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As discussed above, there has been exciting progress in the iden- type I IFN production in pDC. These studies suggest potential targets tification of new receptors involved in nucleic acid sensing and the for the treatment of various immune diseases related to type I IFN. mechanism that the sensors use to distinguish foreign and host The correct magnitude and duration of TLR signaling is essential for nucleic acids. These studies provide a better understanding of appropriate innate immune responses and subsequent adaptive the initiation of innate immune responses by invading pathogens immune responses. The excessive activation of TLR signaling is assoc- and may potentially aid the design or modulation of antiviral iated with the pathogenesis of many autoimmune diseases. In normal treatments. individuals, a number of molecules have evolved that exert negative regulatory effects on TLR signaling.40 Over the past few years, several ACTIVATION AND MODULATION OF INNATE IMMUNE proteins have been described that are negative modulators of TLR 41 42 RESPONSES signaling pathways, including A20, IRAK-M, SOCS-1 (suppressor 43 TLR signaling of cytokine cignaling 1), SIGIRR (single immunoglobulin IL-1R- related molecule),44 ST245 and Tank.46 TLRs have been extensively studied in recent decades for their involvement in the recognition of multiple structures or components of We identified an unexpected role for integrin CD11b; it negatively regulates TLR signaling pathways by mediating the degradation of microbes. TLRs are type I transmembrane molecules characterized 47 by ectodomains containing varying leucine-rich-repeat motifs and Myd88 and TRIF. In addition, two molecules, orphan nuclear recep- cytoplasmic Toll-IL-1 receptor domains, which are required for the tor SHP (small heterodimer partner) and a NOD-like receptor family member NLRX1, have been recently shown to negatively regulate TLR recognition of PAMPs and downstream signal transduction, respect- 48 ively. MyD88 mediates the downstream signaling pathways of various signaling. Yuk et al. reported that SHP represses the transactivation TLRs, with the exception of the TLR3- and TLR4-mediated activation of the NF-kB p65 subunit and suppresses the polyubiquitination of the adaptor TRAF6, which ultimately results in the negative regulation of of IRF3, which signals mainly through a MyD88-independent but 49 TRIF-dependent pathway. For the MyD88-dependent pathway, TLR inflammatory cytokine production triggered by TLRs. Xia et al. and agonists induce the recruitment of MyD88 [myeloid differentiation Allen et al. independently reported the function of a member of the primary response gene (88)] and TIRAP [TIR domain containing nucleotide-binding domain and leucine-rich-repeat-containing adaptor protein], which activates IRAKs (interleukin-1 receptor- (NLR) protein family, NLRX1, as a negative regulator of TLR and associated kinase) and TRAF6 (tumor necrosis factor receptor- RIG-I signaling. NLRs are known as positive regulators of innate immune responses;50 however, new evidence suggests that NLRs can associated factor 6). In combination with the E2 ubiquitin ligase 51 complex of UBC13 (ubiquitin-conjugating enzyme 13) and UEV1A also act as inhibitors of TLR-mediated responses. Xia et al. demon- (ubiquitin-conjugating enzyme variant 1A), TRAF6 acts as an E3 ubi- strated that NLRX1 is rapidly ubiquitinated in response to LPS stimu- quitin ligase and catalyzes its own lysine 63-linked polyubiquitin chain lation, dissociating from TRAF6, and subsequently interacts with the and the NF-kB essential modulator NEMO (also known as IKKc (IkB IKK complex, which inhibits TLR-triggered NF-kB activation. In c addition to the role of NLRX1 in the regulation of TRAF6-NF-kB kinase )). Subsequently, this ubiquitination activates the TAK1 52 (transforming growth factor b-activated protein kinase 1) complex, signaling, Allen et al. provided further evidence that NLRX1 inter- resulting in the phosphorylation of NEMO and the activation of the feres with the RIG-I–MAVS pathway, thus preventing type I IFN and IKK complex consisting of IKKa, IKKb and IKKc (also known as IL-6 responses to viral infection. IKK1, IKK2 and NEMO, respectively) that phosphorylates IkB and The regulators of TLR signaling described above were mainly iden- leads to its dissociation from NF-kB. Free NF-kB translocates into the tified by conventional approaches, such as the screening of inducible nucleus and promotes the expression of pro-inflammatory cytokine genes in response to TLR ligand stimuli or the identification of genes. TAK1 also activates the MAPK (mitogen activated protein unknown components using mass spectrometry. However, the chal- kinase) cascades that lead to the induction of cytokine genes activated lenge is to discover more activators or modulators of TLR signaling by AP-1 (activator protein 1). In the MyD88-independent pathway, using a more effective strategy and to integrate the dissecting signaling 53 TRIF is essential for the induction of non-typical IKKz, IKKe and networks. Recently, Chevrier et al. reported a systematic strategy TBK1 that mediate the activation of IRF3 and the production of through which a series of previously unknown signaling components IFN-b.34 were identified, including Plk2 (Polo-like kinases 2) and Plk4 (Polo- Recently, Nrdp-1, a novel E3 ligase previously discovered by our lab, like kinases 4), mediators of a novel mammalian antiviral response was identified as a positive regulator of the TLR pathway. Nrdp-1 pathway. This strategy combined transcriptional profiling, genetic and induces MyD88 degradation and TBK1 activation to promote type I small-molecule perturbation and unbiased phosphoproteomics. The IFN production.35 In addition, our recent study36 provides new findings are promising for the future investigation of TLRs and other insights into the unexpected role of MHC class II in promoting signaling pathways, and they should lead to the systematic integrated TLR-triggered innate immune responses. We discovered that intracel- mapping of signaling networks. lular MHC class II molecules interact with Btk (Bruton’s tyrosine kinase) via the costimulatory molecule CD40 and maintain the activa- RLR signaling tion of Btk. Activated Btk interacts with the adaptor molecules MyD88 As mentioned above, RIG-I is a cytosolic RNA receptor that triggers and TRIF, thereby promoting TLR signaling.37 A study by Tun-Kyi et innate immune defenses against a variety of RNA viruses through al.38 described the role of prolyl isomerase Pin1 in the promotion of a recognizing 59-triphosphate and/or polyuridine motifs present in TLR-triggered type I IFN response. The authors reported that Pin1, the RNA. The activation of RIG-I-dependent signaling pathways activated by TLR7 and TLR9 agonists, binds and activates IRAK1, induces the antiviral response and the production of type I IFN, which leading to IRF7 activation and type I IFN production. In addition, can activate both innate and adaptive immunity against viral replica- Saitoh et al.39 suggested that the antiviral protein Viperin, induced tion and spread.54 The strength and duration of the RIG-I signal is after TLR7 or TLR9 stimulation, interacts with IRAK1 and TRAF6 and finely regulated to ensure a beneficial outcome in response to foreign promotes the ubiquitination of IRAK1, leading to IRF7 activation and invaders.55 Hayakawa et al.56 recently reported a previously unknown

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role for poly(ADP-ribose) polymerase as a stimulator of RIG-I signal- tissue-inducer cells and cells that produce IL-5, IL-13, IL-17 and IL-22. ing. The study demonstrated that the zinc-finger antiviral protein ILCs are mostly enriched in mucosal tissues and are important for shorter isoform, a member of the poly(ADP-ribose) polymerase innate protection against infectious microorganisms, lymphoid tissue family of proteins, interacts with RIG-I to promote the oligomeriza- formation, tissue remodeling and the homeostasis of tissue stromal tion and ATPase activity of RIG-I, which induces IRF3 and NF-kB cells. Currently, all known ILCs are derived from Id2-expressing ILC activation and type I IFN and cytokine production. This study pro- precursors, and distinct transcription factors and cytokines play essen- vides a potential strategy for enhancing the immune response to viral tial roles in orchestrating the differentiation of the distinct ILCs. infection through the targeting of zinc-finger antiviral protein shorter According to their distinct transcription factor- or cytokine-depend- isoform. ence, cytokine profiles, biological functions and disease associations, Many accessory proteins have been identified that play a critical role the known ILCs are grouped into the following three categories: NK, in mediating the downstream signaling triggered by RLRs, including helper and RORct (retinoid-related orphan receptor ct). The NK ILCs MAVS (mitochondrial antiviral signaling, also known as IPS-1, include conventional cytotoxic NK cells and IFN-c1 ILC1 subsets, CARDIF and VISA),57 TRIM25 (tripartite motif-containing 25),58 which require IL-15 for their development, produce IFN-c and func- STING (stimulator of IFN gene, also known as MITA and ERIS)59 tion to limit infection by viruses and intracellular pathogens. Helper and EYA4 (eyes absent 4).60 MAVS is a critical adaptor for RIG-I, ILCs contain the ILC2 subset that produces abundant IL-13 in res- MDA5 and NOD2 signaling, mediating the activation of IRF3 and ponse to IL-25 and IL-33, and these cells function to control infection the subsequent production of type I IFNs. Despite a growing under- by extracellular parasites. The RORct1 ILCs include lymphoid tissue- standing of the critical role of MAVS in RLR signaling, little is known inducer cells, IL-17-producing ILC (ILC17) and IL-22-producing about the mechanism underlying the activation of MAVS. A very innate cells (ILC22), which require IL-7 for their development, express 61 recent study by Hou et al. demonstrated that the sequential binding heterotrimers of LT-a and LT-b and produce IL-17 and IL-22, respect- of RIG-I to viral RNA (59-ppp RNA) and K63 ubiquitin chains induces ively. These ILCs participate in the host defense against extracellular the formation of large MAVS aggregates, which behave like prions bacteria. The dysfunction of helper ILCs and RORct ILCs is associated with a potent ability to activate NF-kB and IRF3. The authors suggest with allergic diseases and some autoimmune diseases, respectively.63 that a prion-like conformational switch occurs in MAVS that activates Discussed below are some of this year’s latest findings regarding the and amplifies antiviral responses and provides a mechanism to medi- development and function of several ILC subsets. ate robust antiviral responses. Unlike MAVS, STING is required for signaling triggered by both RIG-I and DNA sensors, including DAI but 1 62 Development of RORct ILC not MDA5, to induce type I IFNs. Recently, Chen et al. identified a Distinct transcription factors are essential for the development of the critical role for STAT6 (signal transducer and activator of transcrip- different ILC subsets. For example, the transcription factor NFIL3 tion 6), activated by STING, in antiviral infection. The authors pro- 64 (E4bp4) is required for the development of NK cells, and RORctis vide evidence that STAT6 is recruited by and interacts with STING in 1 65 essential for the development of RORct ILCs, including lymphoid response to viral infection, and the phosphorylation of STAT6 subse- tissue-inducer, ILC22 and ILC17. The identification of transcription quently induces the target genes responsible for immune cell homing. factors or candidate molecules that regulate distinct ILC lineage com- Furthermore, the authors show that STAT6 is required for the antiviral mitment is currently a hot topic. Recently, researchers have discovered response in vivo. The work clarifies the regulation of RIG-I signaling a number of signaling molecules that are involved in the development and reveals a previously unrecognized role for STAT6 in antiviral of ILC subsets. responses. Possot et al. and Lee et al. independently demonstrated that Notch signaling is required for the development of a number of RORct1 ILC Future perspectives for innate signaling subsets. Possot et al.66 determined that Notch2 signaling is specifically There has been substantial progress in our understanding of the ini- required for the development of adult RORct1 ILCs but not fetal liver tiation and activation of innate immune responses to pathogen infec- RORct1 ILCs, whereas Lee et al.67 revealed that Notch is required for tion, especially for novel sensors of cytosolic nucleic acids, as well as the the development of NKp461 ILCs, a subset of the ILC22 family. molecular regulation and crosstalk between the comprehensive signal- Possot et al.66 demonstrated that fetal and adult bone marrow- ing pathways. However, some areas of the innate immune response derived RORct1 ILCs mature in the fetal liver environment and peri- require further investigation. For example, more information regard- pheral organs, respectively. In addition, the study showed that fetal ing the components and regulators of cytosolic PRRs and their down- liver common lymphoid progenitors differentiate into RORct1 ILCs stream signaling pathways and the role of these molecules in activating as they successively acquire the expression of the integrin a4b7 and immune responses in vivo are required. In addition, the relationships chemokine receptor CXCR6, which is accompanied by the loss of B- between the TLR system and cytosolic PRRs and the integration of cell and T-cell potential. Thus, CXCR6 is an additional marker of ILC different signaling pathways between different immune cells remain to lineage commitment. be investigated. Furthermore, additional mechanisms that ensure reli- The ligand-dependent transcription factor aryl hydrocarbon recep- able self and non-self distinction have yet to be discovered. tor (AHR) participates in the regulation of Treg and Th17 cell generation,68 and it plays a critical role in regulating IL-22 production by INNATE LYMPHOID CELLS T cells.69 It has been shown that RORct1 ILCs express the AHR;70 Discovery of ILC however, the role of AHR in the development of ILCs is unknown. Lymphoid cells derived from common lymphoid progenitors include Recently, Kiss et al. and Lee et al. independently demonstrated that B cells and T cells, the major types of lymphocytes that orchestrate AHR is required for the development of intestinal RORct1 ILC and adaptive immunity and ILCs. ILCs are a recently identified family of ILC22 cells, respectively. Kiss et al.71 described the essential role of heterogeneous cell subsets that are developmentally related and evo- AHR in the postnatal expansion of intestinal RORct1 ILC and the lutionarily conserved. This family of cells includes NK cells, lymphoid formation of intestinal lymphoid follicles. The study shows that AHR

Cellular & Molecular Immunology Highlights of the advances in basic immunology in 2011 J Liu et al 201 within RORct1 ILCs is activated by dietary ligands and thus serves DIFFERENTIATION AND FUNCTION OF T-CELL SUBSETS as a molecular link between nutrients and intestinal homeostasis Brief history of the identification of T-cell subsets 67 and immunity. Meanwhile, Lee et al. demonstrated that AHR is In 1986, Mosmann and Coffman discovered the helper T (Th) cells, necessary for the development of ILC22 cells and the formation of Th1 and Th2, based on their distinct pattern of cytokine production postnatal lymphoid tissues including cryptopatches and isolated and function.80 Since then, our knowledge of the differentiation and lymphoid follicles, thus playing an essential role in the host defense function of various T-cell subsets has greatly expanded. Upon recog- 72 against intestinal bacterial infections. In addition, Li et al. demon- nition of the antigen peptide-MHC complex T-cell receptor, naive strated that AHR is highly expressed in intraepithelial lymphocytes CD41 T cells are induced to differentiate into specific T effector cells and plays a crucial role in regulating the maintenance of these cells. in the presence of costimulatory signals provided by antigen-present- Intraepithelial lymphocytes reside in the body’s surfaces, organizing ing cells and a complicated cytokine microenvironment from the an epithelial barrier against infection. Collectively, the studies innate immune and adaptive immune systems. To date, four distinct 1 describe a critical role for AHR in the development of RORct T-cell subsets have been characterized, Th1, Th2, Th17 and iTreg cells, ILCs and intraepithelial lymphocytes, and they establish a link which shape the adaptive immune responses mainly through distinct between dietary compounds, the intestinal immune system, and cytokine profiles and participate in the pathological processes of the microbiota. various diseases. Briefly, Th1 cells produce IFN-c and IL-2 and medi- 73 Accordingly, Sawa et al. recently identified a cross-regulation mech- ate immune responses against intracellular pathogens, whereas Th2 1 anism among intestinal symbionts, adaptive immunity and RORct cells, which produce IL-4, IL-5, IL-9, IL-10 and IL-13, mediate hum- 1 ILCs. The authors demonstrated that RORct ILCs constitutively pro- oral responses and immunity against extracellular parasites including duce most of the intestinal IL-22. Although the symbiotic microbiota helminthes.81 Th17 cells express IL-17A, IL-17F, IL-21 and IL-22 (and and adaptive immunity could inhibit the production of IL-22, epithelial IL-26 in humans) and participate in immune responses against extra- damage restored this function for the benefit of tissue repair. cellular bacteria and fungi as well as multiple autoimmunity processes.82 Treg cells play critical roles in maintaining self-tolerance Novel findings in ILC2 cells and in regulating immune responses through the secretion of trans- The type 2 cytokine–producing innate lymphoid ILC2 subset forming growth factor-b (TGF-b) and IL-10 and by contact- includes nuocytes and natural helper (NH) cells that produce dependent mechanisms.83 The development of the T helper subsets abundant Th2 cytokine IL-13 in response to IL-25 and IL-33. is dictated by their master transcription factors, T-bet (Th1-specific T These cells also express CD127 (IL-7 receptor a-chain), IL-33R box transcription factor) for Th1, GATA-3 (GATA binding protein 3) and IL-17RB and engage in the control of extracellular parasites. for Th2, RORct for Th17 and Foxp3 for Treg cells. Nevertheless, Although ILC2 cells in mice have attracted interest, ILC2 cells in growing evidence has indicated a considerable flexibility and plasticity humans are poorly defined. Recently, Monticelli et al.74 identified a among committed T-cell subsets through complex crosstalk between population of lung-resident ILCs in mice and humans that resem- distinct transcription factors.84 Understanding the developmental bles the phenotype and cytokine profile of ILC2 cells and is critical programs of these T-cell subsets and the mechanisms involved in for airway epithelial integrity and tissue remodeling after infection the regulation of their functions has been a major focus in recent years. with influenza virus. These lung-resident ILC2 cells produce In this section, we will summarize some of the latest discoveries in the amphiregulin following stimulation with infectious agents, which developmental regulation of the distinct T-cell lineages by cytokines promotes epithelial cell proliferation through the EGFR receptor.75 and transcription factors and their roles in different immune res- In addition, Mjo¨sberg et al.76 defined a unique population of ponses and diseases. Special emphasis will be placed on research per- CD1271CRTH21CD1611 ILCs in humans that are potent produ- taining to Th17 and Treg cells. cers of IL-13 in response to IL-25 and IL-33. However, because 1 CRTH2 ILCs accumulate in nasal polyps in chronic rhinosinusitis, Th2 cells: development and trafficking the IL-5 and IL-13 secreted by these cells can potentially induce the GATA-3 is an essential regulator of Th2 differentiation85 and activates symptoms of allergic disease and thus play a pathogenic role in the genes encoding Th2 cytokines through epigenetic modifications respiratory immune responses. including histone acetylation and chromatin remodeling.86 Recently, 77 A recent report by Chang et al. described the function of NH cells the molecular basis for GATA-3 directing the Th2 lineage commit- in airway inflammation, thus describing a previously unrecognized ment has been further clarified by Tanaka et al.87 The study shows that role for innate immunity in viral-induced asthma. The study demon- the DNase I-hypersensitive site 2 (HS2) element, located in the second strated that infection with influenza causes the development of airway intron of IL-4 locus (Il4), functions as a critical enhancer that is strictly hyper-reactivity, a characteristic feature of asthma, independent of the controlled by GATA-3. HS2 is uniquely essential for the production of adaptive immune system but requiring the activation of the IL-13-IL- specific IL-4 but not IL-5 and IL-13. HS2 is a target of GATA-3 that 78,79 33 axis and natural helper cells. regulates the chromosomal modification of Il4, including the tri- methylation of histone H3 at Lys4 and the acetylation of histone H3 Future perspectives for ILC research at Lys9 and Lys14.88,89 There is increasing evidence for the importance of ILCs in the defense The work described above sheds new light on the detailed mech- against invading pathogens as well as lymphoid formation and tissue anism of how GATA-3 functions to determine Th2 commitment at a homeostasis. Continuing research into the diversified phenotype and transcriptional level. In other studies by Kool et al. and Kuroda et al.,a function of distinct ILCs subsets, the regulation mechanism for novel molecular mechanism by which immunogenic particles initiate development of ILCs and the interaction of ILCs with environmental Th2 cell responses is described. Uric acid crystals are a known cause of factors and other immune cells or molecules will further clarify the gout; however, there are few reports of the role that uric acid plays in biological characteristics of this family of cell subsets and their roles in other inflammatory process, especially in T-cell commitment. Kool health and disease. et al.90 provided evidence that uric acid, which is released from

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asthmatic airways, is critical for Th2 cell immunity and alum- and observed. STAT3 binding induces IL-17 and RORct but inhibits house dust mite allergen-induced type 2 immunity in DC in a spleen Foxp3, and IL-2 inhibits IL-17 through promoting STAT5 binding tyrosine kinase- and PI3-kinase d signaling-dependent manner. and limiting STAT3 binding at these sites. Thus, a competition Accordingly, Kuroda et al. also indicated that silica crystals and alumi- between STAT3 and STAT5 binding, controlled by IL-2, modulates num salts induce type 2 immune responses in a NALP3 inflammasome- Th17 cell differentiation. In addition, Maruyama et al.124 reported that independent and PGE2 (prostaglandin E2)-dependent manner.91 Id3 (DNA-binding protein inhibitor 3) plays an opposing role in the Whereas the NLRP3 inflammasome is required for alum-induced adju- differentiation of Treg cells and Th17 cells, as discussed in section 5.4 vanticity,92 these two studies identified an inflammasome-independent (Treg cells: differentiation). pathway through which type 2 immune responses are activated by In addition to transcription factors, a number of cytokines are aluminum salts. These results may help reveal the molecular mecha- involved in the fine-tuned regulation of Th17 cell differentiation. nism behind alum adjuvanticity.93,94 Recently, the leukemia inhibitory factor was reported to be an The migration of Th2 cells from the lymph nodes to peripheral inhibitor of Th17 cell differentiation;105 the administration of tissues is the key step for inflammatory responses; however, the mech- neural progenitor cells ameliorates experimental autoimmune ence- anism regulating the Th2 cell migration is not fully understood. phalomyelitis through the selective inhibition of Th17 cells, and the Recently, two findings have increased our understanding of Th2 cell secretion of leukemia inhibitory factor is responsible for the control trafficking. Islam et al.95 identified a critical role for the CCL8–CCR8 of Th17 cells and experimental autoimmune encephalomyelitis by axis in Th2 cell migration. This study demonstrated that CCL8 is an neural progenitor cells through upregulating SOCS3, which leads to agonist for the chemokine receptor CCR8, which is expressed in IL- the downregulation of STAT3 activity. The study identifies leuke- 51Th2 cells and promotes IL-5-mediated chronic allergic inflam- mia inhibitory factor as a novel regulator of Th17 cell differenti- mation by recruiting Th2 cells in allergen-inflamed skin.96 In addition, ation and provides insights into the mechanisms of the effects of Li et al.97 demonstrated that the extracellular matrix protein-1 is neural progenitor cell in the treatment of neurodegenerative dis- highly and selectively expressed in Th2 cells and is essential for the eases.106 In addition, Solt et al.107 demonstrated that SR1001, a Th2 cell egress from lymphoid tissues through the re-expression of high-affinity synthetic ligand that is specific to both RORa and S1P1 (sphingosine-1 phosphate receptor 1). The work indicates a RORct, significantly inhibits Th17 cell differentiation and function, potential strategy for the treatment of related allergies by influencing thus providing a potential target for the treatment of autoimmune Th2 cell migration.98 diseases.108 IL-23 is required for the complete differentiation and function of Th17 cells;109 however, the factors that mediate the Th17: differentiation and function pathogenic function of Th17 have remained elusive. Studies by Th17 cells and their effector cytokines play crucial roles in infectious, Codarri et al.110 and EI-Behi et al.111 independently identified a inflammatory and autoimmune diseases. Multiple cytokines have critical role for granulocyte-macrophage colony-stimulating factor been implicated in the regulation of Th17 cell differentiation, for in the initiation of Th17-mediated autoimmune neuro-inflam- example, IL-6 and TGF-b potently initiate Th17 cell differentiation. mation induced by IL-23. Using a model of EAE, IL-23 was shown Likewise, IL-21 controls the generation of Th17 cells, and IL-23, IL-1 to induce a positive feedback loop whereby granulocyte-macro- and IL-18 have also been implicated in Th17 cell differentiation. In phage colony-stimulating factor produced by Th17 cells promotes contrast, IFN-c, IL-4, IL-27 and IL-2 negatively regulate Th17 cell antigen-presenting cells to secret IL-23. This study defines a chief differentiation.99 Several transcription factors have been implicated mechanism underlying the important role of IL-23 in inducing in the control of Th17 cell development, such as RORa and RORct, Th17 encephalitogenicity in autoimmune diseases of the central establishing the expression of a Th17 cell-specific gene program. nervous system.112 Foxp3, STAT1, STAT5 and ETS1 (V-Ets erythroblastosis virus E26 Th17 cell-derived cytokines, mainly consisting of IL-17A–F and other oncogene homolog 1) negatively regulate TH17 cell differentiation.100 cytokines, such as IL-22, not only enhance innate defense against infec- Several groups have described in detail the regulation of Th17 cell tion but also mediate inflammatory tissue damage in the pathogenesis differentiation by distinct transcription factors. Dang et al.101 iden- of autoimmune diseases. The secretion and mechanisms of action of tified hypoxia-inducible factor 1 as a key metabolic sensor that favors these cytokines are precisely regulated by the microenvironmental fac- Th17 cell generation, but inhibits Treg cell generation. This study tors surrounding the Th17 cells and the interactions with their recep- shows that hypoxia-inducible factor 1 is induced under Th17 skewing tors.113 Among the IL-17 members and their receptors, only IL-17A and conditions and drives the differentiation of Th17 cells via cooperation its receptor have been extensively studied for their molecular structures, with RORct, STAT3 and p300, whereas hypoxia-inducible factor 1 biological functions and signaling pathways. Recently, Song et al., inhibits Treg cell development by mediating Foxp3 protein degrada- Ramirez-Carrozzi et al. and Chang et al. independently reported the tion. The work demonstrates how metabolic signals regulate the bal- mechanism underlying IL17C function. Song et al.114 and Ramirez- ance between inflammation and tolerance and provide a potential Carrozzi et al.115 demonstrated that IL-17C is induced in colon epithe- therapeutic opportunity for the treatment of diseases.102 Lazarevic lial cells during infection and activates downstream signaling through et al.103 demonstrated that T-bet, a master regulator of Th1 cells, binding to the IL-17RE–IL-17RA complex, leading to the production of inhibits Th17 cell generation by preventing the transcription factor antibacterial peptides and pro-inflammatory molecules by epithelial Runx1-mediated activation of the gene encoding RORct. The inter- cells; thus, IL-17C plays an important role in early innate immunity action of T-bet with Runx1 blocks the Runx1-mediated transactiva- to intestinal pathogens.116 Chang et al.,117 however, demonstrated the tion of Rorc. The STAT proteins selectively regulate T helper cell role of IL-17C in the pathogenesis of autoimmune diseases. IL-17C differentiation, and Yang et al.104 recently elucidated the direct recip- binds and forms a complex with IL-17RE expressed on Th17 cells rocal action of STAT3 and STAT5 in the regulation of IL-17 produc- and subsequently induces the activation of Act1 and IkBf, thus activ- tion by Th17 cells. In this study, the direct binding of STAT3 and ating the Th17 cell response. This work sheds new light on the function STAT5 to multiple common sites across the Il17a–Il17f locus was and signaling pathway of IL-17 and its receptor.

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The phenotypic and functional properties of Th17 cells have been In addition, from an epigenetic perspective, a recent study by Beyer extensively studied in recent years. However, future work that focuses et al.130 revealed the mechanism underlying the shift between effector on the additional transcription factors involved in Th17 differenti- T cell function and suppressive T cell function. SATB1, a genome ation, the additional roles of Th17-derived inflammatory cytokines organizer that regulates chromatin structure and gene expression, and the additional mechanisms of Th17 cells interaction with other was found to be required for establishing effector T cell differentiation cell subsets will broaden our understanding of the developmental and and the induction of effector T-cell cytokines. Foxp3 suppresses clinical significance of Th17 cells.118 SATB1 activity directly through the maintenance of a repressive chromatin state at the SATB1 locus and indirectly through inducing Treg cells: differentiation the binding of microRNAs (miRNAs) to the SATB1 39 untranslated Since the identification of the transcription factor Foxp3, it has region. Therefore, SATB1 is a proposed molecular switch that directs been widely accepted by the immunological community that the Treg cell reprogramming to effector T cells. CD41CD251 T cells are regulatory T cells. Treg cells can be divided into two groups according to their distinct origins; naturally occurring TFR cells versus TFH cells Treg cells that are produced in the thymus from CD41 thymocytes119 TFH cells represent a novel subset that promotes the function of B cells and induced Treg (iTreg) cells that are induced in the periphery from distinguishable from other Th subsets. These cells are characterized na¨ıve CD41 T cells in response to the low-dose engagement of by the significant expression of CXCR5 and their specific location in the TCR, TGF-b and IL-2.120 Despite remarkable advances in the B-cell follicles.131 TFH cells potently stimulate the differentiation of B understanding of the cellular and molecular mechanism of Treg cell cells into antibody-forming cells through the secretion of IL-21, which development and function in recent years, some questions remain. promotes the generation of TFH cells using a feedback mechanism.132 This year, the substantial progress in this field shared a common focus: The dysfunction of TFH cells and their associated molecules, such as the regulation of Treg cell generation. inducible costimulatory molecule or IL-21, may contribute to the Foxp3 is the master transcription factor for the differentiation of pathogenesis of certain autoimmune diseases or immunodeficien- Treg cells, which are essential for maintaining self-tolerance and cies.133 The transcription factor Bcl-6 has been shown to direct the immune homeostasis.121 Recently, much attention has focused on lineage commitment of TFH cells,134–136 whereas the inducible costi- the phenotypic and functional diversity of Treg cells, which is driven mulatory molecule provides a critical early signal for inducing the by the regulation of Foxp3 expression and specific transcription fac- expression of Bcl6 that subsequently induces CXCR5 and regulates tors distinct from Foxp3. A recent study by Cretney et al.122 indicated IL-21 production by TFH cells.137 B cells are required for the main- that the transcription factors Blimp-1 and IRF4 jointly define a novel tenance of Bcl6 and TFH cell commitment. The interfollicular zone is pathway that leads to the acquisition of a particular Treg cell effector the site where germinal center B cell and TFH cell differentiation is function. The study reports that the expression of Blimp-1 defines a initiated. Plasma cells also negatively regulate the TFH cell program population of Treg cells that has an effector phenotype, localizes to through the inhibition of Bcl-6 and IL-21 expression.138 Recently, 139 mucosal sites and produces IL-10. Furthermore, the expression of Morita et al. presented the interesting finding that human blood 1 1 IRF4 is essential for Blimp-1 expression and for the differentiation CXCR5 CD4 T cells may be circulating TFH cells and contain spe- 1 1 of all effector Treg cells, thus describing a previously unknown role cific subsets, such as CXCR5 Th2 and CXCR5 Th17 cells, which for the IRF4–Blimp-1 axis in the effector function of Treg cells and differentially support antibody secretion via IL-21. These authors revealing how distinct transcription factors interact with each other in also propose that an altered balance of TFH cell subsets toward 1 1 an immune network.123 In addition, Maruyama et al.124 demonstrated CXCR5 Th2 and CXCR5 Th17 cells is related to juvenile dermato- that the DNA-binding inhibitor Id3 plays a critical role in controlling myositis, a systemic human autoimmune disease. the differentiation of Treg cells and Th17 cells. They found that the Despite the increasing understanding of the differentiation and deletion of Id3 leads to the defective generation of Treg cells but the function of TFH cells, little is known about how TFH cell numbers enhanced differentiation into Th17 cells. Mechanistically, an Id3 defi- and functions are controlled. Treg cells have been shown to suppress 140 141 142 ciency leads to the defective binding of E2A protein to the Foxp3 Th1, Th2 and Th17 cell responses through interfering with T- promoter and the defective removal of inhibition by GATA-3 at the bet, IRF-4 and RORct signaling, respectively. Recent studies by 143 144 145 Foxp3 promoter. Rorc activation and the subsequent Th17 differenti- Linterman et al., Chung et al. and Wollenberg et al. indepen- ation are also regulated by E2A.125 Thus, the cooperative network of dently identified a unique T-cell subset located in the germinal center Id3, E2A and GATA-3 regulates Foxp3 expression. Interestingly, that shares phenotypic characteristics with TFH cells and conven- 1 Wang et al.126 recently challenged the conventional theory that tional Foxp3 regulatory Treg cells, yet are distinct from both. This 1 GATA-3 negatively regulates Foxp3 expression127 by providing evid- T-cell subset, designated TFR cells, consists of Foxp3 Blimp- 1 high high 1 ence that GATA-3 is essential for Treg cell function and that GATA-3 1 CXCR5 PD-1 CD4 and potently inhibits T cell proliferation promotes Foxp3 expression through binding with Foxp3 elements.128 and TFH cell numbers as well as controlling germinal center B cell 1 A recent study by Beal et al.129 demonstrated that in addition to selection. TFR cells originate from thymic Foxp3 precursors, which transcription factors, the adaptor molecule Ndfip1 influences the dif- further develop in the periphery depending on Bcl-6, SLAM- ferentiation of iTreg cells. In this study, Ndfip1 was shown to play a role associated protein, CD28 and B cells. TFR cells may thus provide in sustaining normal amounts of Foxp3 expressed in iTreg cells. Ndfip1 a potential target for maintaining immune tolerance to prevent 146,147 expression is transiently upregulated during the course of iTreg cell autoantibody-associated autoimmunity. differentiation in a TGF-b-dependent manner and promotes the E3 ubiquitin ligase Itch-mediated degradation of the transcription factor Naive, effector and memory T cells JunB, thus preventing IL-4 production. Therefore, the mechanism One of the research highlights of the last year was the discovery of the underlying the role of TGF-b signaling in iTreg cell differentiation by transcriptional programs that regulate T-cell differentiation into effector inducing Ndfip1 expression to silence IL-4 production is proposed. T cells versus memory T cells. Yang et al. and Ji et al. independently

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identified Id3 as a key transcriptional regulator in controlling effector T et al.170 demonstrated that miR-29 suppressed IFN-c production by cells differentiation into memory T cells. Yang et al.148 reported that a directly targeting the 39 UTR (untranslated regions) of Ifng mRNA. deficiency in Id2 (DNA-binding protein inhibitor 2) or Id3 results in the Furthermore, increased IFN-c production and the more effective loss of distinct CD81 effector and memory populations, whereas Ji clearance of Listeria monocytogenes, as well as enhanced Th1 responses et al.149 consistently demonstrated that the enforced expression of Id3 and greater resistance to mycobacterial infection, were observed in strengthens the recall responses. Ji et al. further demonstrated that the miR-29 sponge-transgenic mice compared with their littermates. transcriptional repressor Blimp-1 represses the expression Id3 in short- miR-29 suppresses immune responses to intracellular pathogens by lived effector T cells and thus limits the ability of the short-lived effector directly targeting IFN-c. A study by Leavy,169 however, demonstrated T cells to persist as memory cells. that the repression of IFN-c production by miR-29 is attributed to the In addition to transcriptional regulators, recent evidence shows that direct targeting of the 39 UTRs of Tbx21 and Eomes, but that Ifng is not the target for rapamycin (mTOR) is critical for memory CD81 T-cell targeted. The transcription factors Tbx21 (encodes T-bet) and Eomes differentiation in mammals. mTOR is an evolutionarily conserved are known to promote IFN-c production independently. Together, PI3-kinase family member that plays a central role in the regulation these data suggest an important role for miR-29 in the regulation IFN- of amino-acid metabolism, energy balance and cell survival. It has c production and provide potential clues for the treatment of inflam- been previously shown that mTOR plays a negative role in memory matory diseases though the elucidation of the exact mechanism of the CD81 T-cell differentiation.150 mTOR functions to promote the suppressive function of miR-29. effector versus memory cell fate of antigen-specific CD81 T cells by Furthermore, Rossi et al. demonstrated that miR-125b is a signature regulating the expression of the transcription factors T-bet and miRNA of naive CD41 T cells and regulates the expression of genes Eomesodermin (Eomes).151 Recently, Li et al.152 further elucidated involved in T-cell differentiation, including IFNG, IL2RB, IL10RA and the critical role of mTOR in homeostatic proliferation-induced PRDM1. The identification of an ‘atlas’ of specific microRNA expres- CD81 T-cell memory and tumor immunity. The inhibition of sion in human lymphocytes and in different subsets through mTOR in CD81 T cells promotes homeostatic proliferation-induced microRNA profiling analysis was also reported.172 In a study by CD81 T-cell memory and anti-tumor effects. Homeostatic prolifera- Oertli et al.,173 miR-155 expression was shown to be required for the tion-induced mTOR enhances transcription factor T-bet and CD122 control of H. pylori infections and infection-associated immuno- expression, which sensitizes IL-15-dependent CD81 T-cell memory pathologies through regulating Th17/Th1 cell differentiation. Blu¨ml formation by inducing the expression of transcription factor Eomes et al.174 also reported an essential role for miR-155 in the adaptive and over T-bet. innate immune reactions, including Th17 polarization, leading to Recently, in addition to its role in the differentiation of memory T autoimmune arthritis. cells, an emerging role for mTOR in directing T-cell activation and Over the past few years, substantial advances have been achieved in differentiation has been reported.153–155 mTOR promotes the differenti- elucidating the role of miRNAs in the development and function of the ation of CD41 T cell into effector cells versus Treg cells in response to immune system. Continuing work concentrating on the identification appropriate skewing conditions.156 The distinct signaling complexes of additional miRNAs involved in immune responses and diseases as mTORC1 and mTORC2 are formed around mTOR. 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