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Kidney International, Vol. 61 (2002), pp. 1935–1946

PERSPECTIVES IN BASIC SCIENCE

The T as a bridge between innate and adaptive immune systems: Implications for the

HAMID RABB

Nephrology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

The as a bridge between innate and adaptive immune explain in vivo observations in kidney disease. Thus, systems: Implications for the kidney. immunologic studies of kidney diseases can lead to new The is classically divided into innate and treatments, as well as expand current immunologic adaptive components with distinct roles and functions. T cells are major components of the . T cells models. are firmly established to mediate various immune-mediated Classically, the immune system has been divided into kidney diseases and are current targets for therapy. Ischemic innate and adaptive components with distinct roles and acute renal failure, a major cause of native kidney and allograft functions [11]. The comprises the dysfunction, is mediated in part by inflammatory components of the innate immune system. However, recent data from ex- nonspecific resistance to , whereas adaptive im- perimental models in kidney as well as , intestine, munity is characterized by specificity and immuno- and implicate T cells as important mediators of ischemia logic memory. In this review, key components of the innate reperfusion injury. These data reveal new insights into the and adaptive immune responses will be discussed, includ- pathogenesis of ischemic acute renal failure, as well as identify ing recent data supporting significant crossover functions novel and feasible therapeutic approaches. Furthermore, the identification of T cells as a mediator of early alloantigen- of select components of each system. New data will then independent injury demonstrates that the functional ca- be presented supporting a role for the T cell as a newly pacity of T cells spreads beyond adaptive into the recognized mediator of the innate both realm of the innate immune response. in kidney and extrarenal organs. I apologize in advance for the inadvertent omission of key references.

There is increasing evidence for the immunopathogen- esis of renal diseases that were previously not recognized INNATE IMMUNE SYSTEM to have an immune basis [1]. Ischemia-reperfusion injury Although it has been long appreciated that host de- (IRI) to the kidney, a major cause of acute native kidney fense depends on both innate and adaptive immune re- and allograft dysfunction, is now established to involve sponses, the main focus of research over components of the immune system [2–7]. In addition, the 30 years has been on the adaptive response [12]. there is increasing awareness of the interrelationship be- More recently, there has been renewed interest in the tween immunologic and non-immunologic factors in kid- innate immune response. Much of the basic work on the ney diseases previously felt to be solely of immune or innate system has been performed in . Drosophila non-immune etiology [8–10]. Chronic progressive renal has been a particularly fertile model, with a well-charac- dysfunction in native kidneys, as well as allografts, typi- terized resistance to microbes employing effector mole- fies conditions where these interrelationships are becom- cules with overlapping functions during morphogenesis. ing evident. A broad overview of the immune response Many Drosophila are up-regulated by septic in- is therefore important for those studying or caring for jury, activating transcription factors of the nuclear factor- the patient with renal disease. At the same time, immune kappa B (NF-␬B) and Rel families [12]. Close evaluation paradigms developed from in vitro studies may not fully of these elucidated striking similarities with cy- tokine-induced NF-␬B dependent acute phase response Key words: T cell, acute renal failure, ischemia reperfusion, innate genes in mammals. Another , the moth, was the immunity, adaptive immunity. original source of discovery of inducible peptides [13]. Over 400 of the Received for publication July 11, 2001 and in revised form February 4, 2002 innate immune system subsequently have been identified Accepted for publication February 5, 2002 in different species. Study of the response of the African  2002 by the International Society of Nephrology mosquito Anopheles, which harbors the deadly Plasmo-

1935 1936 Rabb: The T cell and innate and adaptive systems dium malaria parasite, has also yielded considerable in- [11]. These -associated structures are produced formation on mechanisms through which the innate im- by pathogens, are usually essential to the , mune system mounts successive multisite responses both and are usually present throughout entire classes of locally and systemically [14]. These comparative studies pathogens. Receptors for pathogen-associated molecules with the human innate response have had a major impact are found on , dendritic cells, and B cells. in our current understanding of this field. Once bound, these receptors directly activate effector The innate “hard-wired” immune system mounts an functions. Well-characterized receptors of the innate im- immediate response that is stereotypic, generic in nature, mune system include mannan-binding (which pro- and is felt to lack immunologic memory. Innate immunity motes complement activation) [22], and the has evolutionary links to phyla. The mam- (facilitates endocytosis of pathogens malian innate system is composed of plasma proteins and presents the derived proteins by MHC molecules (such as complement), cells [, macrophages on the surface) [23]. and natural killer (NK) cells] and physical barriers (Fig. 1) Recently, a new family of receptors, called “toll” re- [15]. The is the major that responds ceptors, has been invoked in the initiation of innate im- rapidly to or trauma. Neutrophil mobility to munity. These transmembrane proteins were originally sites of inflammation and the ensuing are identified in Drosophila as regulators of dorsoventral enhanced by specific IgG and complement polarity [24]. At least 10 mammalian toll receptors have (C3) [16]. These facilitate phagocytosis. Low been identified, and the toll-like receptor-4 (TLR-4) is molecular weight () attract and ac- important in recognition and respon- tivate neutrophils, as well as initiate and mediate in- siveness [25, 26]. TLR-4 also plays an important role in flammatory responses for both innate and adaptive im- innate immunity to respiratory syncytial [27] and mune systems [17]. Complement amplifies the innate Treponema family [28]. Furthermore, this re- immune response through three different pathways: two ceptor mediates macrophage migration inhibitory factor independent of (Ab)-antigen (Ag) complexes, (MIF) signaling in macrophages [29]. TLR-4 and other and the third requiring Ab-Ag complexes for activation. toll-like receptors are fertile area of investigation for The final effector mechanism for all three is the forma- new insights into innate immunity. tion of the active membrane attack complex. The alterna- tive pathway is activated via interaction with specific ADAPTIVE IMMUNE SYSTEM membrane components of pathogens, while the classic pathway requires specific Ab bound to antigen for activa- The adaptive immune response is felt to have devel- tion. Complement also serves as an immunoregulator of oped approximately 450 million years ago when a transpo- the immune response. Complement activation is tightly son that carried the primitive variants of the recombinase controlled by inactivation of free complement in plasma. activating genes, RAG-1 and RAG-2, became inserted In addition, complement is regulated by several inhibi- into the germ line of jawed [30]. The adaptive tory proteins, such as C1 inhibitor and decay-accelerating immune system responds to antigenic challenge with factor. Defects in these inhibitors lead to diseases such specificity that requires antigen receptors that can recog- as hereditary angioedema and paroxysmal nocturnal he- nize millions of different molecular structures. At rest, moglobinuria. Complement also has been linked to the the population of expressing a particular pathogenesis of ischemic injury in kidney [18] as well as antigen receptor specific to a particular antigen is rela- other organs [19, 20]. Other leukocytes comprising the tively small. These lymphocytes constitute memory cells innate system that have cytotoxic abilities include mono- for that specific antigen. Upon re-exposure to a particular cytes and NK cells. These cells can manifest cytotoxicity antigen there is enormous expansion of the specific lym- without prior sensitization to the target. Natural killer phocytes. Conversely, after resolution of the antigenic cell-mediated killing appears to involve specific HLA challenge, reductions in population occur recognition [21]. Killing occurs when the NK cell encoun- with residual memory cells that store information. Such ters cells devoid of specific HLA molecules normally learning augments the rapidity and vigor with which the responsible for cytotoxicity-inhibiting signal. NK cells organism responds to subsequent antigenic challenge. also produce cytokines that directly affect B and T cell The adaptive response is localized with precise homing function. mechanisms of lymphocytes [31]. The innate immune system recognizes and responds T and B cells are the major components of the adaptive to a restricted set of highly conserved structures common immune system, and both express highly specific antigen to different pathogens [11]. These common structures, receptors on their surface (Fig. 2). B cells produce spe- called pathogen-associated molecular patterns, include cific antibodies which neutralize pathogens, facilitate lipopolysaccharide, , bacterial DNA, double- phagocytosis by opsonization, and activate complement. stranded RNA, lipoteichoic acid, mannans and glucans The T cell response is mediated by the T cell receptor Rabb: The T cell and innate and adaptive systems 1937

Fig. 1. Innate immunity. The innate system provides the initial defense against infection and injury. The primary components of innate im- munity are: (1) physical and chemical barriers; (2) phagocytic cells (neutrophils and macro- phages), natural killer (NK) cells and possibly dendritic cells; (3) proteins, including members of the and other mediators of inflammation; and (4) cytokines that regulate and co-ordinate many of the ac- tivities of the cells of innate immunity. (Repro- duction of this figure in color was made possi- ble by Texas Biotech Corp., Houston, Texas.)

Fig. 2. Adaptive immunity. There are two types of adaptive immunity: humoral and cell- mediated. is mediated by antibodies that are produced by B lympho- cytes. It is the principal defense mechanism against extracellular microbes and their tox- ins, with secreted antibodies binding to mi- crobes and to assist in their elimination. Cell mediated immunity is mediated by T cells, with dendritic cells playing important roles in . T cells can function by various methods: (1) activating macrophages to kill phagocytosed microbes; (2) directly de- stroy infected cells; and (3) by releasing cyto- kines and alter the milieu around them. (Re- production of this figure in color was made possible by Texas Biotech Corp., Houston, Texas.)

(TCR). The TCR responds to antigen peptides presented among individual genes for the receptor domains re- on macrophages following phagocytosis of pathogens ferred to as variable (V), diversity (D) and joining (J) (such as bacteria), and to peptides from cytosolic patho- regions of the TCR and immunoglobulin, a process de- gens (such as ) presented on infected cells. Most noted somatic recombination [32]. The association of T cells produce a multimeric TCR with ␣ and ␤ chain, multiple different V, D and J regions leads to the forma- while a few express the gamma (␥) and delta (␦) chains. tion of up to 1012 or more specific receptors. This random The enormous repertoire of antigen receptors is gener- process occurs early in the process of B and T cell devel- ated during immunologic development by rearrangements opment prior to contact with antigen. When a specific 1938 Rabb: The T cell and innate and adaptive systems

Fig. 3. Antigen dependent and antigen inde- pendent T cell activation. Several integral mem- brane proteins are involved in antigen recog- nition and functional responses expressed on T cells. They specifically bind ligands present on antigen presenting cells (APCs) and in- crease the strength of adhesion between a T cell and an APC. Many accessory molecules may transduce biochemical signals to the inte- rior of the T cell and they are able to regulate immune responses. Recent evidence suggests that T cells also can be activated by antigen independent pathways. Oxygen free radicals, cytokines and RANTES have all been impli- cated in directly causing T cell activation. (Re- production of this figure in color was made possible by Texas Biotech Corp., Houston, Texas.)

Fig. 4. Potential mechanisms of T cell involve- ment in ischemia-reperfusion injury (IRI). Lo- cal effect: In the T cells can bind to macrophages, , neutrophils and en- dothelium. This amplifies the microcirculatory sludging and “no-flow” state. Within the inter- stitium, T cells can contact APCs or be acti- vated by injury signals with an APC. Adjacent to , T cells can directly damage epi- thelial cells, as well as regulate epithelial cell function. Distant effect: T cells may be exerting an effect also from a distant site such as the , marrow, lymph nodes and . T cells lodged in these sites could re- lease cytokines and chemokines that are hav- ing an effect on inflammatory mediators in the kidney. Furthermore, these distant sites are where T cells traffic for education, expansion and deletion. (Reproduction of this figure in color was made possible by Texas Biotech Corp., Houston, Texas.)

receptor has been expressed, it becomes the only antigen and respond to the infection or injury. The innate im- recognition structure expressed by that lymphocyte and mune system has traditionally been viewed as a temporiz- its progeny. The process of activation and proliferation ing defense mechanisms, acting until the lymphocyte can of a lymphocyte after encountering an antigen is termed take over, and that the innate immune system basically , which is the basic property of the adap- primes the adoptive response [11]. However, the interac- tive immune response. It takes three to five days for tions between the two are much more complex. Recent enough clones to be produced and differentiate into ef- evidence implicates relationships between the innate im- fector cells [11]. It is in this early phase that effector mune response as determinants whether the antigen, mechanisms of the innate immune system are activated foreign or native, will induce an immune response. Rabb: The T cell and innate and adaptive systems 1939

CD4ϩ cells function as both helper and regulatory a localized and rapid release of IFN-␥, which precedes cells, fulfilling these roles via direct cell-cell interactions ␣␤ T cell activation by hours and days. Thus, it has been as well as by secretion of many cytokines. One model felt that ␥␦ responses may influence the ␣␤ response of T cell activation posits that at least two different sig- [40]. Gamma delta T cells can also modulate nals are necessary to activate T cells. The first signal production by NK cells [41]. Thus, the ␥␦ cell may be an arises from TCR binding of the complex of antigen frag- important link between innate and adaptive immunity. ment and HLA. The second involves a costimulatory There are many other examples of links between innate signal mediated by, CD80 (B7-1) and CD86 (B7-2) mole- and adaptive immunity, including the observation that cules (Fig. 3) [11]. In the absence of CD80 or CD86 toll receptors of the innate immune system induce the costimulation, antigen recognition leads to inactivation B7 variants, CD80 and CD86, which in turn mediate or of the T cell. adaptive immune responses [11].

CURRENTLY ESTABLISHED LINKS EVIDENCE SUPPORTING A ROLE FOR BETWEEN THE INNATE AND ADAPTIVE T CELLS AS A MEDIATOR OF INNATE IMMUNE SYSTEM IMMUNITY IN EXTRARENAL ORGANS Key links between innate and adaptive immune sys- The immune response to tissue injury is (1) immediate, tems include the antigen presenting dendritic cells (DC), and (2) does not require alloantigen stimulation. There found at the sites of entry into the body, for example, are many modes of tissue injury where the innate im- , , kidney, and liver, bind and ingest invaders. mune system is activated: ischemia reperfusion injury, DCs are components of the innate immune system that burns, crush injuries, envenomation, etc. IRI is becoming then transfer information to the adaptive immune system increasingly well characterized both clinically and scien- [33]. DCs also are activated by other components of the tifically, and will be the focus of the remainder of this innate system, which allow DC to carry antigen to lymph discussion. The pathogenesis of IRI is complex, but in- nodes (LNs), where it is presented to T and B cells to flammation is an established feature. Extensive studies initiate the adaptive response. Dendritic cells release on IRI have been performed in the heart, brain and -␥ (IFN-␥), which then further triggers a cas- intestine. It is believed that oxygen free radicals and cade of antigen-nonspecific responses mediated by the mitochondrial products are important initiators of cellu- innate immune system. Penfield et al have found that lar and soluble components of the innate immune re- during renal IRI, dendritic cells migrate into the kidney sponse during IRI [42]. Complement is activated, partic- [34]. This could be a central event by which the innate ularly via the alternative pathway, generating fragments and adaptive immune systems are linked in renal IRI. such as and C5a. This process leads to a release of Natural killer cells are a subset of lymphocytes found , activating factor, a host of cytokines, in blood, lymphoid tissue, and especially spleen [35]. NK with attendant increase in vascular permeability. Neu- cells lack the TCR for antigen recognition and possess trophils and are activated, with up-regula- the ability to kill tumor cells or host cells infected by tion of the adhesion molecules including CD11/CD18, virus. NK cells do not require prior contact with target ICAM-1 and P-. Neutrophil/platelet aggregates to develop cytolytic properties, though NK cells promote microvascular plugging (“white clot”) and emi- can acquire specificities using their that binds gration of neutrophils into tissue results in local destruc- to IgG-coated target cells. NK cells use numerous pore tion. Macrophages also infiltrate in a more delayed fash- cell toxins. T cell, particularly CD4ϩ cells, can stimulate ion, and likely contribute to repair. Thus, the PMN is the NK cell functions. Therefore, NK cells, though members central leukocyte observed in tissue necrosis following of the innate immune response, have a number of ways ischemia. Based on the above, the T cell, seen only in of interacting with adaptive immune responses. small numbers during necrosis, would not be expected T cells bearing the gamma-delta (␥␦) form of the T cell to play a major role in this process, at least on theoretical receptor are a minor population of T cells in lymphoid grounds. Traditional paradigms concluded that, “the organs and the circulation, but a prominent population lymphocytes plays very little, if any, role in the acute in skin, intestine and [36]. Gamma-delta T cells can phases of inflammation, but principally contributes to recognize structures presented by and reactions in chronic long-standing inflammatory pro- stressed cells, as do macrophages [37]. Presentation of cesses” [43]. Recent data, however, challenge this model. antigen to ␥␦ T cells bypasses the usual processing path- The persistent clinical dilemmas of managing patients ways required for peptide association to MHC molecules with IRI and new experimental tools have fueled in- [38]. There is also a primary sequence difference between creased research in the early inflammatory response dur- amino acids that make up ␥␦ TcRs and the conventional ing IRI. There is now both indirect and direct evidence ␣␤ T cells [39]. Gamma delta cells are characterized by that T cells are important mediators of IRI, even in the 1940 Rabb: The T cell and innate and adaptive systems

Table 1. Evidence for pathogenic role of T cells in gut, heart and lung ischemia/reperfusion injury Model Species Intervention/Effect Reference Liver Cold ischemia Rat protective Kawano 1996 [44] Decreased leukocyte adhesion Liver IRI Rat Tacrolimus protective Garcia 1998 [45] Intestine Decreased leukocyte adhesion Liver Partial lobe Mouse T cell deficient (nu/nu) mice protected Zwacka 1997 [46] subacute phase CD4 depletion protective in wild types T cells modulated neutrophil infiltration Liver IRI Mice T cell deficient (SCID) mice protected Horie 1999 [47] CD4ϩ population more important than CD8ϩ cells in this effect Liver IRI Rat FTY 720 with cyclosporine protective, but FTY 720 alone was not Mizuta 1999 [48] protective Liver Ex vivo cold Mouse nu/nu mice protected Le Moine 2000 [49] ischemia IL-10 protective Resident T cells important Intestine IRI Rat Cyclosporine and rapamycin protective Puglisi 1996 [50] Heart Transplant Rat Mycophenolate protective Valentin 2000 [51] Decreased leukocyte adhesion Heart Rat Cytotoxic T cells activated that kill non-ischemic myocytes Varda 2000 [52] Lung Cold IRI Canine Increased natural killer activity in lavage Adoumie 1992 [53] increased MHC II expression in 24 hours Lung Cold IRI Swine Platelet-activating factor blockade protective, possibly by Nikbakht 2000 [54] decreasing T cell activation Lung Transplant Rat Antithrombin III treatment protective, possibly by decreasing Okada 1999 [55] T cell proliferation Brain Focal ischemia Rat Tacrolimus but not rapamycin nor cylcosporine protective; im- Sharkey 1994 [56] munophilin pathway invoked

absence of alloantigen, and that they act in the early to reduce hepatic IRI injury in rats [44]. These effects injury period. These observations shift the classical role appeared to be independent of phagocytic of the T cell, suggesting that it may play an important activity. In a separate study using FK506 in both liver role in the early inflammatory response rather than func- IRI as well as mesenteric IRI in rats, tissue protection tioning exclusively as a component of the adaptive im- correlated with decreased intercellular adhesion mole- mune response. cule-1 (ICAM-1) and P-selectin expression as well as There are abundant experimental studies in many non- decreased leukocyte rolling [45]. The authors attributed renal organs identifying the presence of T cells after IRI. the protection afforded by FK506 to its effect on adhe- These will not be enumerated. However, it should be sion molecule expression. However, other interpreta- noted that though numerous studies have demonstrated tions also may be valid, as FK506 is known to exert a delayed influx occurring after the clear functional dete- its effects by altering ischemia-induced ceramide and rioration of tissue, T cells have generally not been sought apoptosis signaling [57]. A study using cyclosporine A or rigorously identified with definitive techniques. Very and rapamycin, which both impair T cell activation as early times (first few minutes, hours) have rarely been their main functions, demonstrated attenuated small examined. Furthermore, descriptions do not usually dis- bowel IRI in rats [50]. The first direct proof of the role tinguish intravascular accumulation of T cells in the early for T cells in IRI came from a series of elegant studies no-reflow state of IRI, compared to the overt extravasa- on mouse liver. In the subacute phase of liver injury (16 tion out of the microcirculation. This is an important to 20 hours postischemia), a marked preservation of liver distinction, and one that has not been thoroughly ad- function was found in T cell-deficient athymic mice com- dressed to date. Presence or absence of the T cell is pared to wild type BALB/c strain [46]. This was associ- further confounded by the potential for T cells to be ated with a marked decrease in neutrophil infiltration. sequestered in sites of inflammation as “innocent by- Adaptive transfer of wild type T cells into the athymic standers.” Therefore, the following focus will be on stud- (nu/nu) mice restored the neutrophil-mediated injury. ies that have used techniques to assess cause and effect, In vivo depletion of CD4ϩ cells, but not CD8ϩ cells in as well as transferability. wild type mice was also protective. Similarly, mice with Some of the most convincing evidence for T cell severe combined immunodeficiency (SCID) also were involvement in renal IRI comes from studies of the gut protected from liver IRI, and that T cell adoptive transfer, (Table 1) [44–56]. The calcineurin inhibitor FK506 (ta- particularly of CD4ϩ cells, restored injury [58]. These crolimus) used to prevent T cell-mediated allograft rejec- results were confirmed and extended by experiments that tion as well as other autoimmune diseases, was found found that T cell-deficient mice to be relatively resistant Rabb: The T cell and innate and adaptive systems 1941 to liver IRI. In this ex vivo model of IRI, it was the resident effect of FK506. Both rapamycin and FK506 compete and not infiltrating T cells that played the important role, for the same common binding site on lymphocyte FK and -10 (IL-10) modulated this T cell re- binding . sponse [49]. A potential mechanism by which T cells mediated IRI was revealed by examining the effects of EVIDENCE SUPPORTING A ROLE FOR CD4ϩ cell reconstitution into severe combined immuno- T CELLS AS A MEDIATOR OF INNATE deficient mice (SCID) with bowel inflammation. In this IMMUNITY IN THE KIDNEY work, CD4ϩ cells, particularly those whose surface ex- pression of CD45RB was high, were found to up-regulate Unlike heart or gut, where neutrophils are well estab- a variety of T helper-1 (Th1) and macrophage-derived lished to be important mediators of IRI, the role of cytokines, as well as leukocyte adhesion molecules [59]. neutrophils in renal IRI is controversial and not as well Attempts to further elucidate the mechanisms of T cell- established [62]. Treatment of rats [63] and mice [64] mediated up-regulation of cell adhesion have been con- with neutrophil depleting antiserum reduced postische- ducted in vitro on hypoxic human umbilical cells mic acute renal failure. However, use of neutrophil de- (HUVEC). T cell adhesion to HUVECs stimulated sub- pleting serum in rats undergoing renal IRI was not found sequent neutrophil adhesion to HUVEC, as well to be protective by other groups [65, 66]. Elegant ex vivo as up-regulation of vascular cell adhesion molecule I techniques have demonstrated that infused neutrophils (VCAM-1). -␣ (TNF-␣) was felt can synergize with ischemia to cause acute renal failure to be the key factor that linked T cell adhesion to VCAM-1 [67]. Certain compounds that protect renal function and expression [60]. tubular structure during experimental acute renal failure An early study of the effects of IRI on lung trans- attenuate neutrophil influx into injured kidney, prompt- plantation using canines found that within one to four ing the interpretation that the compounds worked by hours of reperfusion, there was a marked influx of lym- inhibiting neutrophil infiltration. This has been demon- phocytes (and neutrophils) accompanied by an increase strated in the case of adenosine receptor blockade, which in lectin-mediated cytotoxicity and cyto- protects renal function after IR and attenuates myelo- [53]. The authors also found an increase in MHC peroxidase activity, a marker of tissue neutrophils [68]. class II expression, concluding that IRI could render Interleukin-18 blockade in mice also results in tissue pro- lungs more susceptible to rejection. Another interven- tection and decreased levels [69]. Alpha- tional study with indirect evidence that T cells were medi- melanocyte stimulating hormone (␣-MSH) markedly re- ating lung IRI was performed in swine. Pig lung undergo- duced renal neutrophils and attenuated renal IRI [7]. ing IRI was protected from edema by platelet activating However, subsequent study of ␣-MSH demonstrated that factor antagonism, which also decreased T cell activation the mechanism of action was independent of neutrophils and infiltration [54]. In a separate study using rat lungs [70]. Others have recently demonstrated that many of undergoing IRI, antithrombin III, with potent antithrom- the studies that identified neutrophils in acute renal fail- botic and inflammatory properties was found to be pro- ure mistakenly evaluated macrophages instead: myelo- tective; however, this agent also decreased T cell prolifer- peroxidase, chloroacetate esterase, and “neutrophil- ation, a mechanism of protection being speculated in the specific mAb HIS-48” all cross-reacted with macro- interpretation of the results [55]. In the heart, though phages [71]. Furthermore, both in sheep [72] and in rats much evidence exists for leukocyte mediation of reperfu- [73] neutrophil infiltration into postischemic kidney has sion events and the presence of lymphocytes postischemia, been dissociated from direct role in tissue injury. It is there is little supportive evidence yet for a direct role of quite possible that the neutrophil has been overesti- T cells. Abnormalities are found in circulating T cells mated as a pathophysiologic factor in renal IRI due to associated in humans with myocardial ischemia or in- the prominent influx observed in experimental models. farction [61]. An elegant mechanistic study of myocardial A series of experimental studies demonstrated an im- infarction using rats found that T cells became activated portant role for the leukocyte adhesion molecules CD11/ by the cardiac injury, and also retained a memory re- CD18 and ICAM-1 in renal IRI [3, 4, 64, 74, 75]. These sponse against myocytes [52]. Though there are abun- studies also were interpreted as demonstrating an impor- dant data on T cell infiltration after brain IRI, only lim- tant role for neutrophils during IRI, but this was not ited data to date found a direct role for the T cell. conclusive due to the observations of many groups that Administration of FK506 in a rat model of focal cerebral induction of did not lead to protection from occlusion significantly reduced infarct size [56]. IRI [58]. In fact, it was observed that of severe neutro- Interestingly, the related immunophilin, cyclosporine as penia was not protective in the identical model that well as the T cell activation inhibitor rapamycin did not CD11/CD18 and ICAM-1 blockade worked (abstract; protect at the doses administered. In fact, rapamycin Mendiola et al, J Am Soc Nephrol 4:741, 1993). A possi- given together with FK506 blocked the neuroprotective ble interpretation is that CD11/CD18 or ICAM-1 block- 1942 Rabb: The T cell and innate and adaptive systems

Table 2. Indirect evidence for a role for T cells in renal IRI Model Species Findings References Biopsies Human Mononuclear cells, not neutrophils, in vasa recta during acute renal failure Solez 1979 [76] IRI Rats Tacrolimus pretreatment protective, potentially by regulating TNF release Sakr 1992 [77] IRI Rats CD11/CD18 (expressed on T cells as well as other leukocytes) blockade protective. Rabb 1994 [3] Neutrophil depletion not protective in parallel studies IRI Rats CD11/CD18 & ICAM-1 blockade protective, need to give intervention early for effect Kelly 1994 [4] IRI Rats ICAM-1 blockade protective during severe ischemia Rabb 1995 [74] IRI Mice ICAM-1 knockout protective Kelly 1996 [64] Reduced myeloperoxidase content of injured kidney IRI Rats ICAM-1 antisense oligonucleotides protective Haller 1996 [75] Transplant Human Anti-CD11a/CD18 therapy decreased delayed graft function Hourmant 1996 [78] IRI Rats Mycophenolate protective when combined with bioflavinoids Jones 2000 [79]

ade, which has profound effects on T cell function, could post-ischemia (within 24 hours) despite the use of differ- have also worked via action on T cells (Table 2) [3, 4, ent antibodies to detect T cells. When CD4ϩ cells defi- 64, 74–79]. As in liver IRI, FK506 was found to also cient in CD28 or IFN-␥ were adoptively transferred, attenuate experimental renal IRI in rats [77]. In addition, injury was not restored, thus revealing the important mycophenolate mofetil, which has for the most part re- role for CD28 and IFN-␥ in renal IRI [84]. To evaluate placed azathioprine in most clinical T cell suppression if alloantigen-independent factors could activate T cells regimens, also confers protection from renal IRI [79]. in a nephrotrophic manner, T cells were incubated with Furthermore, a significant reduction in early injury after renal epithelial cells in hypoxia-reoxygenation condi- cold renal IRI was afforded by blockade of the T cell tions, resulting in increased T cell adhesion to renal epi- CD28-B7 costimulatory pathway with CTLA4Ig (a re- thelial cells compared to that in normoxic conditions combinant fusion protein that contains a homolog of [83]. More recently, use of the B7-1 Ab to CD80 but CD28 fused to an IgG1 heavy chain) [80]. This work was not B7-2 Ab to CD86 also abrogated renal IRI in rats, extended to a long-term model of progressive protein- demonstrating that is was likely the B7-1 pathway that uria in uninephrectomized rats that underwent cold IRI was blocked in the CTLA4Ig work [86]. These data fur- [81]. CTLA4Ig treatment on the day of injury, as well ther strengthened the argument for role for T cells in as delayed treatment one week beyond ischemia (but not renal IRI. Thus, there is now ample evidence from differ- four weeks), was effective in reducing proteinuria [81]. ent labs using diverse techniques of an important role One interpretation was that CTLA4Ig could have had for T cells in the immediate response to renal ischemic other effects besides involving specific T cell activation injury (Table 3) [79–84, 86]. As yet there are insufficient [82]. To test the hypothesis if T cells were directly in- data to extend these conclusions to humans. However, volved in renal IRI, mice deficient in CD4 and CD8 cells it is important to note that in human kidney biopsies of were evaluated and found to be protected from renal acute renal failure, mononuclear leukocytes, not neutro- IRI [83]. Knockout mice, however, can have additional phils, have been observed in the vasa recta [76]. In addi- changes besides the targeted disruption. Therefore, an- tion, studies using thymoglobulin induction to prevent other T cell knockout mouse strain was used, the athymic allograft rejection “serendipitously” reduced delayed nu/nu mice. This mouse was also protected from renal graft function, the major manifestation of renal IRI in IRI [84]. Furthermore, adoptive transfer of T cells into the cadaveric transplant (abstract; Goltz et al, Trans- these mice restored ischemic injury-potentially fulfilling plantation 67:S388, 1999). the “transferability” that Koch required among his clas- sic postulates [85]. To identify the relative contribution of CD4 and CD8 T cell subsets in renal IRI, individual POTENTIAL MECHANISMS BY WHICH THE CD4 and CD8 knockout mice were studied, with the T CELL COULD BE A MEDIATOR OF THE CD4 knockout showing a marked protection from both INNATE IMMUNE RESPONSE SYSTEM renal injury and mortality after IRI [84]. Adoptive trans- The most widely accepted model of the immune re- fer of the wild-type CD4ϩ cells into these knockout sponse is the “self–non-self” model, where the immune mice also led to a worsening injury phenotype, directly response recognizes exogenous signals that represent a demonstrating the importance of CD4ϩ cells in renal form of non-self. However, an emerging model is the IRI. Surprisingly, the neutrophil and macrophage in- “danger” model, which proposes that the signals initiat- filtration into postischemic kidney was not affected by ing the immune response are inherent in the normal either the nu/nu or CD4 knockout, nor the adoptive body tissues themselves [87]. The self–non-self model as transfer. Very few infiltrating T cells were seen early well as danger model propose that antigen presenting Rabb: The T cell and innate and adaptive systems 1943

Table 3. Direct evidence for a pathogenic role for T cells in renal IRI Model Species Findings Reference Cold ischemia Rat CTLA-4 Ig protective, reduced induction of inflammatory genes Takada 1997 [80] IRI Mouse CD4/CD8 KO mice protected, hypoxia-reanoxia alone sufficient to activate T cells to increase Rabb 2000 [83] adhesion to kidney IRI Mouse Athymic nu/nu & CD4 Ϫ/Ϫ mice protected, T cell transfer restores injury; neutrophil and Burne 2001 [84] macrophage infiltration dissociated from protection IRI Rat Anti-B7-1-Ab protective DeGreef 2001 [86]

cells (APCs) must be activated. However, while the self– shown to directly activate T cells [89]. RANTES up- non-self model is based on the view that a non-self signal regulation has been shown to occur in renal IRI, so this is essential, the danger model proposes that activation is one possible mechanism for T cell activation in the of an APC depends on the health of the cells in its absence of antigen [90]. Another stimuli now demon- neighborhood. Thus, a foreign entity that does no injury strated to be capable of activation T cells and leading will not evoke a response, while a self-entity presented by to up-regulation of pro-inflammatory genes are oxygen APCs will evoke response when accompanied by injury. free radicals [91, 92]. Oxygen free radicals are one of Pre-packaged alarms could be mitochondrial products the most widely recognized products of tissue injury, normally inside the cell, mannose (also found normally particularly IRI, and could be playing an important role inside the cell), RNA, DNA, and inducible signals such in the T cell activation. T cells, when incubated with renal as heat proteins and toll receptors [87]. The danger epithelial cells from the same strain of inbred mouse, model also proposes that each tissue has a set of effector C57BL6, become activated when hypoxia-reoxygenation classes it prefers, so that local responses can be tapered. occurs, and increases their adhesion to these renal cells Thus, a T cell being activated and involved in IRI could [83]. Similarly, T cells exposed to hypoxic endothelial be interpreted by the danger model as a response to cells in culture also become activated and increase their APCs becoming activated by injury, and then traveling adhesive phenotype, in part due to the production of to draining lymph nodes and up-regulating costimulatory TNF by the hypoxic cells [93]. molecules needed to activate T cells. After the initial Thus, a strong theoretical and experimental frame- reaction by the T cells and other inflammatory pathways, work exists to explain the findings of the T cell being an complete remodeling would render the tissue tolerant. important mediator of IRI. However, what is not clear However, if remodeling was not adequate, a continued is how the T cell participates in the injury process. T cell T cell-mediated memory response to the injury would products are important for the optimal expression of occur, resulting in smoldering inflammation with cycles endothelial adhesion molecules, which in turn recruit of repair, which in the long run would lead to fibrosis. and activate [47]. Therefore, it is possible This is very consistent with what we observe in the native that T cells mediate IRI via amplifying inflammation, in kidney subject to injury that, once injured, seems to particular facilitating phagocyte recruitment. However, progress inexorably to end stage fibrosis and failure. the role of the neutrophil in renal IRI is still not fully Similarly, a marginal single kidney allograft with a long defined [58]. Furthermore, neutrophil infiltration into cold ischemia time, after the initial acute renal failure, postischemic kidney can be dissociated from the effects would be expected to gradually deteriorate over time, of T cell manipulation [84]. Administration of the selectin- particularly if other insults were superimposed, such as ligand inhibitor, TBC 1269, which acts on both T cells from hypertension or proinflammatory effects of filtered and neutrophils, markedly protected rat kidney structure proteins. and function after ischemia without halting neutrophil One major question that arises when trying to under- trafficking to postischemic kidney [94]. The observations stand the mechanisms underlying the role of the T cell that brisk leukocyte trafficking into tissue can occur de- in mediating IRI is the nature of the process by which spite tissue protection from injury has been found in the T cell gets activated. Normally, one would expect the other disease models, including [95]. requirement of an alloantigen in the context of co-stimula- The T cell has been well established to have an effect tory signals [88]. In IRI without the presence of an alloan- on renal tubular epithelial cells, and the damage to these tigen, such as in native kidney IRI, one could invoke the cells is the hallmark of IRI, or acute tubular necrosis. unveiling of a self-antigen presented by an APC that However, very few T cells are seen around the epithelium was normally not exposed to the immune system, but in IRI, unlike in acute , making it somehow expressed during tissue injury. Recently, T cell less likely that a direct tubular epithelial toxicity can activation has been demonstrated to occur totally inde- explain the profound effects. Given the amplification pendently of antigen. The RANTES has been effects of just a few T cells and the microvascular in- 1944 Rabb: The T cell and innate and adaptive systems

flammation that characterizes IRI, it would not be sur- Chronic allograft nephropathy (CAN), the leading prising if the effects of T cells were in the blood vessels challenge in long term graft function, may be influenced themselves, with active engagement of platelets, phago- by early changes that result from IRI [100]. Thus, inter- cytes, endothelium and soluble factors (Fig. 4). Increas- ventions to decrease early necrosis and prevent un- ing evidence has linked T cells with vasoactive sub- wanted T cell activation may be useful to prevent CAN. stances, including angiotensin II [96], and thus the T cell Native kidney progressive renal disease, be it from diabe- could have an effect on renal hemodynamics. tes, hypertension, chronic glomerulonephritis or polycys- The T cell lifespan is characterized by circulation tic kidney disease, is characterized by an interstitial through blood and lymphoid tissue. Though it would be mononuclear cell infiltrate that correlates highly with conceptually simpler if the T cell had a direct effect rapid progression. Neither the factors that lead to this in IRI that required adhesion with the cells that were lymphocyte infiltration into the interstitium, nor the ef- dysfunctional, an indirect and/or distant effect may well fects of this smoldering lymphocyte activity are known. be occurring. T cells lodged in spleen, local lymph nodes In addition, important cytokines implicated in the patho- or could well have a role. However, we genesis of progressive renal failure, such as transforming did not find a protection from renal IRI in the splenecto- growth factor-␤ (TGF-␤), have a crucial role in T cell mized aly/aly mouse [97], which lacked spleen and lymph functions and may well interplay. Recently, mycopheno- nodes. Therefore, absence of these lymph organs was late, an immunosuppressive compound widely used in insufficient to alter the course of IRI (Yokota and Rabb, organ transplantation, has been shown to decrease pro- unpublished data). If T cells did work from a distance, or teinuria and renal injury in chronic progressive renal mediated IRI via the production of cytokines, an obvious failure models, suggesting a potential role for T cells question is whether this occurs via the classic T cell TH1 in this alloantigen independent process [101–103]. The (IL-2, IFG) or TH2 (IL-4) pathway. T cell polarization recognition of an important role for T cells in the early into one of these pathways underlies the pathogenesis injury response to ischemia also should stimulate new of a number of diseases from leprosy to schistosomiasis. basic research into T to explain how the Asthma is characterized by a deleterious TH2 response, T cell is participating in the innate immune response. while acute transplant rejection is mainly a TH1 response [98]. However, an array of overlapping cytokines is seen ACKNOWLEDGMENTS in IRI, which clearly does not pinpoint one pathway This work was supported by NIH R01 DK54770 and NKF Clinical versus the other. One strategy to evaluate this question Scientist Award. The author is indebted to Drs. Joseph Handler, Chris is to examine mice that cannot fully polarize into either Lu and John Hotchkiss and for helpful suggestions during manuscript the TH1 (STAT-4) or TH2 (STAT-6) pathways [99]. preparation, Ms. Vanessa Schlinger and Dr. Melissa Burne with tables Recent data demonstrate that the STAT-6 deficient and figures, and Ms. Jan Lovick with references. Reproduction of Figures 1 to 4 in color was made possible by Texas Biotech Corp., mouse is markedly susceptible to renal injury and mortal- Houston, Texas. ity after IRI, suggesting a protective effect of the TH2 pathway in IRI. This suggests the possible existence of Reprint requests to Hamid Rabb, M.D., Division of Nephrology, Ross 970, 720 Rutland Ave., Johns Hopkins Hospital, Baltimore, Maryland a “balancing” T cell phenotype that normally prevents 21205, USA. the full expression of IRI–a “yin/yang” homeostatic E-mail: [email protected] mechanism (abstract; Yokota et al, J Am Soc Nephrol 12:4158A, 2001). REFERENCES 1. 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