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Published online before print May 13, 2005
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Department of Immunology, The Scripps Research Institute, La Jolla, California
1 Correspondence: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail: noras{at}scripps.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTION: HOMEOSTATIC...THE SELF-TOLERANT T CELL...ACCESS TO SELF-ANTIGEN/MHC...LYMPHOPENIA-INDUCED HOMEOSTATIC...A NOVEL ROLE FOR...CONCLUDING REMARKSNOTEREFERENCES |
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Key Words: homeostatic proliferation • lymphopenia • autoimmunity • nonobese diabetic mouse
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INTRODUCTION: HOMEOSTATIC PROLIFERATION IN T CELL POPULATION DYNAMICS |
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TOPABSTRACTINTRODUCTION: HOMEOSTATIC...THE SELF-TOLERANT T CELL...ACCESS TO SELF-ANTIGEN/MHC...LYMPHOPENIA-INDUCED HOMEOSTATIC...A NOVEL ROLE FOR...CONCLUDING REMARKSNOTEREFERENCES |
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The current understanding of lymphopenia-incurred homeostatic proliferation derives largely from experiments in which T cells are adoptively transferred into immune-deficient [usually recombinase-activating gene (RAG)- or CD3
-deficient] or irradiated animals. These model systems mimic situations of extreme T cell deficiency and involve large-scale lymphoid reconstitution by transferred T cells. Discordance exists in the ability of certain T cell specificities to undergo homeostatic proliferation, which reflects their access to limiting amounts of antigen and their affinities for self-peptide/major histocompatibility complexes (MHC) [6
7
8
9
]. A number of bacterial and viral infections also induce lymphopenia [10
, 11
] of variable severity, ranging from the profound CD4+ T cell deficiency imparted by human immunodeficiency virus [12
] to milder and transient lymphopenia caused by influenza virus [13
]. Severe lymphopenia is also observed clinically following chemo- or radiotherapy. Age-related fluctuations in the T cell pool follow a predictable pattern, and T cell lymphopenia is a feature of the young [14
] and the elderly, where thymic involution results in markedly impaired T cell output with progressive age [15
]. This review describes the association that exists between lymphopenia, compensatory homeostatic expansion, and the subsequent development of autoimmunity.
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THE SELF-TOLERANT T CELL REPERTOIRE IS SHAPED INTRA- AND EXTRATHYMICALLY |
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TOPABSTRACTINTRODUCTION: HOMEOSTATIC...THE SELF-TOLERANT T CELL...ACCESS TO SELF-ANTIGEN/MHC...LYMPHOPENIA-INDUCED HOMEOSTATIC...A NOVEL ROLE FOR...CONCLUDING REMARKSNOTEREFERENCES |
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Thymic output encourages a diverse TCR repertoire with the capacity for responding to foreign antigens. Selection processes in the thymus allow emergence of T cells with low affinity for self-antigens and self-MHC, and those potentially self-reactive cells with high affinity are eliminated [17
]. The CD4+ and CD8+ T cells that emigrate from the thymus possess a large array of clonally distributed TCRs for antigen recognition in the context of MHC class II and I MHC molecules, respectively [18
]. According to one estimate, diversity of the human T cell repertoire is >2 x 106 TCR ß chains with the potential to combine with >100 TCR 
chains [19
]. The memory T cell pool is less diverse than the naïve compartment but still contains possible TCR ß chains in the order of 105–106 [19
].
Thymic emigrants persist as naïve cells [20
] or clonally expand in the periphery [5
]. Thymus emigrants continuously renew the naïve T cell pool [21
]. Mice grafted with increased numbers of thymi do not present with proportionate increases in naïve T cell numbers, indicating tight peripheral homeostatic regulation [22
]. In contrast, naïve T cells in a depleted lymphoid compartment go through a burst-like sequence of divisions and in many cases, lose their naïve qualities and acquire some memory-like characteristics following extensive division [7
, 21
, 23
24
25
26
27
]. Homeostatically expanded T cell subsets up-regulate surface expression of some typical memory markers such as CD44, Ly6C, CD122 [interleukin-2 receptor ß (IL-2Rß)], and CD132 [common 
chain (c)] and present with decreased expression of CD45RB on CD4+ T cells [7
, 25
, 26
, 28
]. However, homeostatically dividing cells lack expression of acute activation molecules CD69 and CD25 (IL-2R). The assertion that T cells proliferating under lymphopenic conditions are similar to authentic memory cells was tested by Goldrath and colleagues [29
], who compared the gene-expression profiles with those of memory T cells induced in a conventional, antigen-driven response. Homeostatically expanded cells exhibited stable gene expression profiles that mirrored those of memory cells; however, they expressed attenuated levels of genes associated with cell-cycle progression and cytotoxic T cell function. Progeny of homeostatically expanded CD8+ T cells are capable of acquiring effector function, including cytolysis and interferon- (IFN-) production upon activation with foreign antigen or anti-CD3 monoclonal antibody [24
25
26
, 30
]. Akin to conventional activation, homeostatically expanding cells also harbor an enormous proliferative capacity; quantitation of CD4+ T cell proliferation in syngeneic, athymic recipient mice has demonstrated the capability for an 8 x 105-fold increase in T cell numbers [31
].
Homeostatic proliferation has been studied in neonatal mice to gain insight into T cell population dynamics in a physiologically occurring lymphopenic environment [27 ]. Newborn mice rely on thymus-dependent and peripheral means to populate the periphery, which is largely devoid of T cells at birth [14 ]. Thymectomy experiments have demonstrated that the timely emergence of T cell populations from this organ within the first few days of life is under stringent developmental regulation [32 ]. Although the first T cells are observed to inhabit the lymph nodes at embryonic days 18–20 [33 ], adult percentages of CD4+ T cells are not present until day 7 postpartum in lymph nodes and day 15 in spleens [14 ]. Thymic export [34 ] and homeostatic expansion [27 , 35 ] participate in the attainment of full T cell numbers in neonates. Naïve CD4+ T cells from adult donor mice undergo vigorous proliferation upon transfer into neonatal hosts, in contrast to similarly transferred cells in adult recipients with a "full" T cell compartment, which do not proliferate. Neonatal and adult CD4+ T cells proliferate to a similar extent when transferred into lymphopenic adults [36 ], showing that the lymphopenic host environment, rather than the age of the transferred cells, dictates the capacity for homeostatic proliferation. The availability of IL-7 and the presence of MHC/peptide complexes are required for homeostatic proliferation in neonatal lymphoid compartments [4 , 27 , 35 ]. IL-7 and TCR/MHC-derived signals are widely recognized as necessary for naïve T cell survival and/or expansion, whether the lymphopenic state is physiologically occurring (as in neonates) or experimentally induced in adult animals [37 38 39 40 41 42 ].
In the young immune system, high thymic output and peripheral T cell turnover promote a balance between clonal diversity and expansion of cells with overlapping specificities [43 ]. Aging results in immunological senescence that results from progressive thymic involution and restricted replenishment of the naïve T cell pool. Homeostatic proliferation of pre-existing specificities in the periphery then becomes the dominant influence for sustaining the demand for new T cells [44 , 45 ]. This shift toward peripheral expansion leads to reduced TCR repertoire diversity [46 ]. Indeed, human studies have shown that individual CD4+ and CD8+ clones are expanded in the elderly, reflecting simplification of the T cell repertoire [47 48 49 50 ]. A reduction of the TCR Vß diversity also occurs in mice after 12 months of age [51 ]. The aged murine T cell compartment displays peripheral clonal expansions that are exacerbated by deprived thymic contributions. Thus, age-related diminishment of thymopoiesis profoundly influences the ultimate constitution of the T cell pool.
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ACCESS TO SELF-ANTIGEN/MHC COMPLEXES AND CYTOKINES REGULATES T CELL REPERTOIRE DIVERSITY |
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TOPABSTRACTINTRODUCTION: HOMEOSTATIC...THE SELF-TOLERANT T CELL...ACCESS TO SELF-ANTIGEN/MHC...LYMPHOPENIA-INDUCED HOMEOSTATIC...A NOVEL ROLE FOR...CONCLUDING REMARKSNOTEREFERENCES |
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The fact that T cell competition regulates homeostatic expansion is exemplified by a definitive study from Barthlott et al. [58
] using a model of inflammatory bowel disease. T cell-deficient RAG-1–/– mice develop gut pathology and wasting disease upon adoptive transfer of naïve CD45RBhi CD4+ T cells. It is interesting that cotransfer of high numbers of TCR transgenic T cells of an unrelated specificity completely protects mice from disease. In fact, disease protection afforded by a number of TCR transgenic populations is correlated directly with an increased propensity for homeostatic proliferation in vivo and with elevated surface expression of CD5 [58
]. In the thymus, the negative regulatory molecule CD5 is up-regulated on thymocytes that have experienced vigorous stimulation by self-peptide/MHC [59
, 60
]. It is interesting that CD5 expression levels are also positively correlated with the homeostatic expansion potential of peripheral T cells [61
]. Barthlott et al. [58
] found that inoculation of RAG-1–/– mice with a polyclonal population of competitively adept CD5hi cells significantly delays the onset of wasting disease in comparison with recipients of CD5lo T cells. These results show that homeostatically proliferating, high-affinity T cells can out-compete pathogenic T cells in a lymphopenic host. The repertoire diversity of a reconstituted lymphopenic host is positively correlated with the numbers of naïve CD4+ T cells, which are transferred initially [3
]. Moreover, homeostatic expansion of transferred T cells is much more extensive in mice harboring a less-diverse repertoire as a result of less competition for antigen. Comparison of polyclonal and TCR transgenic cells with various affinities for self-peptide/MHC has revealed that a high affinity for self-ligands conveys a homeostatic advantage [8
, 62
]. Another integral parameter is the abundance of peptide-MHC complexes, which is reflected in the rate of T cell homeostatic proliferation [8
]. TCR affinity differences are a plausible explanation for the finding that some TCR transgenic T cells do not proliferate upon transfer to lymphopenic hosts, despite the fact that the host conditions do promote their survival [5
]. Similar heterogeneity is also found among polyclonal naïve CD4+ or CD8+ T cells, as only 
30% proliferate within 1–2 weeks in a lymphopenic host [55
].
It is interesting that lymphopenia-induced T cell expansion is initiated by the same peptides that induce their positive selection in the thymus [28 , 54 , 55 ], indicating that T cells in the periphery maintain their ability to respond to self. T cells appear to compete directly for self-ligands; memory cells of a particular specificity can effectively inhibit proliferation of newly transferred T cells of the same but not of a different specificity [3 ]. Along these same lines, homeostatic proliferation of naïve CD4+ and CD8+ T cells is impeded in MHC class II- and class I-deficient hosts, respectively [41 , 54 , 63 64 65 66 ]. Reliance on self-peptide/MHC for maintenance of the peripheral T cell pool has been demonstrated elegantly using lymphopenic hosts that lack the H2-M protein and thus possess MHC molecules (I-Ab) that exclusively present class II-associated invariant chain as the self-antigen [54 , 55 ]. Transferred polyclonal, naïve T cells do not proliferate in these hosts, providing proof for the association between expression of selecting ligand and homeostatic proliferation.
Perhaps the most interesting aspect of this requirement for self-peptide and self-MHC relates to the implications that this poses for autoimmunity. The aforementioned studies [8 , 62 ] demonstrate that the highest affinity T cells out-compete their counterparts and thus have the potential to dominate the repertoire as a consequence of lymphopenic incidents. In lymphopenia, T cells have increased access to higher densities of peptide-MHC ligands and increased dwell times with antigen-presenting cells (APC). Completeness imposes limits on the size that any particular self-reactive population can achieve through competition for access to self-ligand on APC [6 ]. Among the possible APC subsets, dendritic cells (DC) are likely candidates for presenting the self-peptides involved in homeostatic expansion. Not only are DC appreciated for their roles in tolerance induction [67 ] but are also the only APC that form physical clusters with T cells in the steady-state in the absence of deliberate antigenic immunization [68 ], conditions where homeostatic expansion could occur. A prototype strain for homeostatic expansion experiments, RAG–/– lymphopenic mice lack B cells, ruling out an obligatory role for this APC type. Conversely, the lymphocyte subset deficiencies these mice present with would impose reliance on particular APC types and reduced concentrations of cytokines that may alter APC maturation and TCR triggering. Thus, although model systems involving T cell transfers into genetically immune-ablated recipients are useful for pinpointing the general roles of DC, they cannot be taken as a verbatim representation of the normal mechanisms of homeostatic expansion.
Apart from an indispensable contribution of antigen/MHC interactions, the second instrumental factors in T cell homeostasis are members of the IL-2 family of cytokines, which are defined based on the fact that their receptors each use c. These cytokines include IL-2, IL-4, IL-7, IL-9, IL-15 [69
, 70
], and most recently, IL-21 [71
]. The shared c component of these cytokine receptors is vital for T cell homeostasis, as underscored by the finding that c-deficient mice exhibit a perturbation of lymphoid tissue development and an age-related accumulation of T cells with an activated phenotype [72
73
74
]. Although c is a shared receptor component for signal transduction, it mediates divergent homeostatic effects when engaged by different cytokines [75
]. In addition to c, the receptors for the individual cytokines each possess their own distinct ligand-binding chains. For example, the receptors for IL-2 and IL-15 contain c and IL-2/IL-15Rß (CD122) [69
]. Each of these cytokine receptors also has a unique chain [IL-2R (CD25) and IL-15R] to form heterotrimeric receptors. In contrast, the receptor for IL-7 is a heterodimer comprised of the IL- 7R chain (CD127) and the c. Shared use of the c receptor component by these cytokines confers mutual signaling through Janus kinase 3 [76
, 77
], and the distinct receptor subunit allows qualitatively different intracellular signals to be transduced. As a result of these precise commonalities and differences in signaling pathways, members of this cytokine family have a generalized involvement in T cell growth and survival, and each conveys distinct effects on expansion and contraction of the repertoire [69
].
IL-7 has gained notoriety as the essential cytokine in T cell homeostasis. IL-7 is a critical survival factor for CD4+ and CD8+ naïve T cells [37 , 38 , 78 ]. IL-7 also allows naïve T cells to undergo homeostatic proliferation [37 , 38 ]. Whether IL-7 has a nonredundant role in memory T cell homeostasis has evolved into a more complex issue, as evidence suggests that IL-7 alone is not responsible for survival or homeostatic expansion [37 , 79 ]. IL-7 acts cooperatively with IL-15 in the maintenance of the CD8+ memory pool, such that homeostatic expansion is still enabled in the absence of one of these cytokines, provided the concentration of the other is not limiting [2 , 79 ]. Indeed, several lines of evidence have substantiated the prominent role of IL-15 in basal proliferation (i.e., in T cell-replete hosts) and in homeostatic reconstitution in lymphopenic situations [2 , 79 80 81 82 ]. Although not obligatory for lymphopenia-induced expansion, these studies show that IL-15 is absolutely required for memory CD8+ T cell maintenance in lympho-replete hosts. There is evidence to suggest that naïve and memory CD4+ T cells have similar requirements for proliferation in lymphopenic hosts, namely TCR-MHC interactions and IL-7 [83 ]. The stromal cell-derived chemokine CC chemokine ligand 21 (CCL21) is also a positive regulator of CD4+ T cell homeostatic expansion. Ablation of CCL21 expression ameliorates homeostatic expansion of transferred T cells in lymphopenic recipient mice, whereas genetic overexpression promotes their proliferation [84 ].
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LYMPHOPENIA-INDUCED HOMEOSTATIC EXPANSION PRECIPITATES AUTOIMMUNITY |
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TOPABSTRACTINTRODUCTION: HOMEOSTATIC...THE SELF-TOLERANT T CELL...ACCESS TO SELF-ANTIGEN/MHC...LYMPHOPENIA-INDUCED HOMEOSTATIC...A NOVEL ROLE FOR...CONCLUDING REMARKSNOTEREFERENCES |
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+) phenotype [86
]. Reconstitution of thymectomized neonatal mice with whole splenocytes can resolve autoimmune sequelae through restoration of CD4+ CD25+ T cell numbers, a conclusion that was based on the ineffectiveness of CD25-depleted splenocytes [87
]. A number of other model systems have also documented the inhibitory effects of CD4+ CD25+ on activation-induced proliferation and effector functions of "conventional" CD25– T cells in experiments where regulatory cells were observed to restrain the unbridled activation of pathogenic clones (refer to [88
] for a recent review of this topic). Another viewpoint has emerged recently that depletion of regulatory T cells cannot be credited as directly causative of autoimmunity in model systems involving T cell adoptive transfers into immune-deficient hosts [58 ]. Indeed, experiments pertaining to regulatory T cells in autoimmunity have largely involved cellular transfers into lymphopenic hosts, most frequently RAG–/–, severe combined immunodeficiency (SCID), or nu/nu mice. The incidence and severity of autoimmune disease are then compared between recipients that were reconstituted with inocula, containing or lacking the CD4+ CD25+ component. Lymphopenia-induced autoimmunity is also relevant to the environment created by day 3 thymectomy, as well as in irradiated, cyclosporine A- or antibody-treated animals, which can all be rendered susceptible to a spectrum of autoimmune diseases (reviewed in [32 ]). Hence, reinterpretation of past results from the perspective of homeostatic expansion may now be warranted. In the example presented by day 3 thymectomy, one can envisage that the resulting state of lymphopenia results in deferral to homeostatic expansion as the sole means for populating the periphery. Once again, reliance on pre-existing T cells and stimulation via self-MHC/peptide would allow the emergence of autoreactive cells. Indeed, it has been formally demonstrated that reduced thymic output can be compensated for by increased survival and homeostatic expansion of peripheral T cells [45 ]. Another important point is that although treatment of lymphopenic hosts with CD4+ CD25+ cells can abrogate autoimmunity induced by cotransferred CD25– cells, depletion of CD25+ cells from T cell-replete animals only rarely evokes de novo autoimmunity [5 ]. The fact that lymphopenic conditions are required to observe the inhibitory function of regulatory T cells in certain models of autoimmunity strongly implicates a contribution of homeostatic expansion. These lines of evidence indicate that immune tolerance mechanisms are multilayered, and their relative roles likely hinge on the experimental conditions of autoimmunity. McHugh and Shevach [89 ] exemplified this point in their demonstration that absence of CD4+ CD25+ T cells is insufficient to cause autoimmunity in a lymph-replete host strain but requires a second set of autoimmune-provoking signals provided by lymphopenic conditions or strong antigenic stimulation through a relevant TCR. Notably, cotransferred CD4+ CD25+ and CD4+ CD25– T cell subsets each proliferate vigorously in lymphopenic hosts, indicating that regulatory T cells do not directly impede lymphopenia-induced expansion and likely act at a later phase in the genesis of disease. The existence of dual mechanisms of tolerance breakdown is evident in the alymphoplasia (aly) mouse strain that exhibits multiorgan autoimmunity as a result of defective thymic stromal elements [90 ]. T cells from this strain homeostatically expand and induce autoimmunity upon adoptive transfer into immune-deficient recipients. Disease is also transferrable by transplanting aly embryonic thymus into athymic nude mice through mechanisms involving homeostatically expanding effector T cells as well as impaired production of CD4+ CD25+ regulatory T cells by the aberrant thymic microenvironment [90 , 91 ]
Type 1 diabetes (T1D) susceptibility and protection are also correlated with lymphopenia and immune reconstitution, respectively, under a variety of other experimental conditions. A correction of the pre-existing lymphopenic state also provides a novel explanation for the fact that generalized immune-stimulatory regimens protect from T1D. Immunization with complete Freund’s adjuvant, comprised of immune-stimulatory mycobacterial cell-wall constituents, protects diabetes-susceptible nonobese diabetic (NOD) mice from diabetes [92 ] and corrects their T cell lymphopenic state [93 ]. Thymectomy [94 ] or cyclosporine A treatment [95 ] of neonatal NOD mice accelerates diabetes onset. Conversely, the chemotherapeutic agent cyclophosphamide causes massive lymphocyte apoptosis and is widely used to accelerate T1D onset in NOD mice, potentially enabling a dramatic expansion of effector T cells that is motivated by severe lymphopenia and repertoire limitations. The BioBreeding rat spontaneously develops T1D as a result of a mutated lyp genetic locus, which is known to confer lymphopenia and increased homeostatic expansion of T cells (reviewed in [96 ]). Autoimmunity in lupus-prone BXBS mice is associated with a Y-chromosome-associated gene that confers increased homeostatic proliferation of self-reactive T cells [97 ]. These studies reinforce the idea that homeostatic proliferation of T cells is facilitated by availability of space provided by an autoimmune-prone genetic background.
An abundance of clinical data also supports an association between lymphopenia-induced homeostatic expansion and autoimmune disease. Lymphopenia has also been identified in patients with T1D [98 ], systemic lupus erythematosus (SLE) [99 ], and Sjorgen’s syndrome [100 ] and in autoimmunity precipitated by viral infection [101 ]. Long-term thymectomized myasthenia gravis patients present with mild T cell lymphopenia and restricted T cell repertoire diversities that are associated with the subsequent development of SLE [102 ]. Oligoclonality of peripheral T cells is also a characteristic of rheumatoid arthritis (RA) patients [103 104 105 ]. Expansion of randomly selected T cell clones occurs at 10- to 20-fold higher frequencies in RA patients compared with controls [106 ]. Naïve and memory T cells in patients with RA have shortened telomeres in comparison with T cells from age-matched, healthy individuals, indicative of an extensive, replicative history [107 ]. These prematurely senescent T cells in RA patients acquire distinct functional attributes that confer effector potential, including apoptosis resistance, natural killer (NK) cell-like features, and cytotoxic abilities [108 , 109 ]. Based on these lines of evidence, the underlying mechanism of autoimmunity in RA is believed to reflect an age-disproportionate decline in thymic activity and accelerated homeostatic expansion of naive T cells to compensate for the deficiency [110 , 111 ].
Patients with T1D present with disturbed lymphocyte homeostasis in the predisease stage and in overt disease. A hallmark feature of the peripheral blood of prediabetic, newly diagnosed, and at-risk patients is an increased prevalence of activated T cells, particularly within the CD8+ subset [112 , 113 ]. Furthermore, reduced overall T cell counts in peripheral blood of diabetic children and their healthy siblings have also been reported [114 ], suggestive of lymphopenia, early in the course of disease. Imbalances in expression of naïve versus memory T cell markers have also been reported, including a generalized overexpression of the CD45RO memory marker on lymphocytes from diabetic children and their siblings [114 ] and an increased prevelance of T cells that coexpress CD45RA (naïve marker) and CD45RO [115 , 116 ]. Accumulation of double-positive cells may reflect a partial stage of activation in the transition from naïve to memory T cells. Taken together, these data are consistent with the notion that T cell lymphopenia, activation, and increased memory cell formation are events in the evolution of T1D. Whether these T cell changes are indeed attributable to homeostatic expansion remains unproven, as the ability to make such formal demonstrations in human studies is limiting.
Studies in T1D patients and the NOD mouse model concur with the notion that autoimmunity is polygenic. This raises the concept that the response to a given diabetogenic autoantigen should not be considered sufficient for development of autoimmunity. However, lymphopenia alone is also insufficient for the development of autoimmunity. This is exemplified by the fact that autoimmunity is not a recognized complication of organ and bone marrow transplantation, although these procedures commonly use lymphodepletion as a tactic to achieve tolerance. Homeostatic expansion following transplantation also occurs under the cover of maintenance-immune suppression, which is speculated to affect the availability of the trophic factors needed for emergence of a pathogenic repertoire. Conversely, T1D is thought to be triggered by viral infection, based on the considerable association between Coxsackievirus infection and development of autoimmune diabetes [117 118 119 120 121 ]. It can thus be speculated that lymphopenia may be virally induced and provides a window of opportunity for expansion of self-destructive cells in individuals with disease-predisposing susceptibility genes.
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A NOVEL ROLE FOR IL-21 IN T CELL HOMEOSTASIS AND AUTOIMMUNITY |
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TOPABSTRACTINTRODUCTION: HOMEOSTATIC...THE SELF-TOLERANT T CELL...ACCESS TO SELF-ANTIGEN/MHC...LYMPHOPENIA-INDUCED HOMEOSTATIC...A NOVEL ROLE FOR...CONCLUDING REMARKSNOTEREFERENCES |
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c-related cytokine family, is well-recognized in the context of its potency in promoting T and B cell proliferation and NK cell cytotoxic activity [122
]. The receptor for this cytokine (IL-21R) has been identified in resting peripheral B cells, activated peripheral blood mononuclear cells, certain T, B, and NK cell lines, and in germinal centers of human lymph nodes [122
]. Structural analyses of the IL-21R have revealed its composition as a heterotrimer of , ß, and c subunits. Signal transduction is mediated through the ß and c subunits while the component facilitates high-affinity binding. IL-21 expression is generally associated with situations of overt activation. IL-21 exerts autocrine influences on proliferation of CD4+ T cells in collaboration with anti-CD3-mediated signals [123
]. Moreover, T helper cell type 1 (Th1) responses and cytotoxic T lymphocyte activity can be augmented by IL-21 [124
], although there are conflicting data in which IL-21 specifically curtails Th1 immunity [125
]. Our laboratory has identified a novel function for IL-21 in homeostatic expansion and autoimmunity [93 ]. The NOD periphery qualifies as mildly lymphopenic, and as a result, compensatory expansion of transferred and endogenous T cells is enabled. Emergence of these expanding T cell populations is correlated with severe islet inflammation in individual NOD mice and direct pathogenic potential of these cells upon adoptive transfer into NOD-SCID recipient mice. Homeostatically proliferating cells in NOD mice are CD44+ and IL-21R+ and exhibit an effector phenotype. Significantly, NOD mice harboring the C57BL/6-derived Idd3 genetic interval (which encompasses the IL-21 gene) are disease-resistant, are not lymphopenic, and do not share this effector population in common with NOD. NOD mice have markedly up-regulated expression of IL-21R on memory T cells, increased IL-21 mRNA levels, and increased responsiveness to this cytokine in vivo. As T cells do not receive survival (memory-creating) signals through IL-21, this unstable situation favors unbridled replication leading to replicative senescence and the continual redirecting of the T cell repertoire toward environmentally generated self-epitopes. In this manner, excess IL-21 appears to drive an unending circuit that leads to autoimmunity. Figure 1 contrasts the factors involved in lymphopenia-induced autoimmunity in NOD mice and other models of experimental autoimmunity with the normalcy of T cell homeostasis in the B6.Idd3.NOD strain.
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genes [128
]. Despite the severely limited repertoire of potentially pathogenic T cells, transgenic NOD mice develop autoimmunity, marked by an equivalent presence of pathogenic CD8+ T cell specificities in the islets. Thus, extremely limited precursor frequencies cannot circumvent diabetes susceptibility in NOD mice as a result of the high efficiency of T cell expansion events.
An important question raised by this work is the nature of the signals conveyed via IL-21 and the intracellular T cell signaling alterations that characterize the NOD strain. IL-21 signaling involves activation of signal transducer and activator of transcription 1 (STAT1) and STAT3 [71
, 129
]. IL-21-induced STAT3 DNA binding in T cells induces gene-expression patterns related to Th1 responses, including expression of IFN-, the transcription factor T-bet, and the signaling intermediate myeloid differentiation factor 88 [129
]. STAT1 signaling has been affiliated with T-bet and IFN- expression [130
]. It is striking that NOD T cells express high levels of tyrosine-phosphorylated STAT3, particularly in pancreatic lymph nodes [93
]. In contrast, signaling pathways activated by the other c-binding cytokines, namely IL-7 and IL-15, activate STAT5 [129
, 131
]. Activation of STAT5-related signaling by IL-7 and IL-15 is followed by increased expression of the antiapoptotic protein bcl-2 or bcl-xL and enhanced cellular survival [132
]. STAT5 has a prominent role in homeostasis of CD8+ memory T cells, whereas STAT5-deficient and transgenic mice have reduced and increased numbers of these cells, respectively [133
]. Overall, these lines of evidence attest to the fact that memory cell formation and stability of the T cell repertoire are regulated by the balance of signals received from various c-binding cytokines. Therefore, in a milieu of excess IL-21-IL-21R interactions, the signals received by NOD T cells would confer increased instability, fueling the syndrome of autoimmunity in the NOD mouse.
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CONCLUDING REMARKS |
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TOPABSTRACTINTRODUCTION: HOMEOSTATIC...THE SELF-TOLERANT T CELL...ACCESS TO SELF-ANTIGEN/MHC...LYMPHOPENIA-INDUCED HOMEOSTATIC...A NOVEL ROLE FOR...CONCLUDING REMARKSNOTEREFERENCES |
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c-related cytokines in an effort to replenish the lymphoid compartments. Studies in the NOD mouse have provided a mechanistic basis for lymphopenia-induced autoimmunity, which is founded in altered T cell proliferation and survival signals mediated by IL-21. |
NOTE |
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TOPABSTRACTINTRODUCTION: HOMEOSTATIC...THE SELF-TOLERANT T CELL...ACCESS TO SELF-ANTIGEN/MHC...LYMPHOPENIA-INDUCED HOMEOSTATIC...A NOVEL ROLE FOR...CONCLUDING REMARKSNOTEREFERENCES |
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Received January 25, 2005; accepted April 11, 2005.
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REFERENCES |
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TOPABSTRACTINTRODUCTION: HOMEOSTATIC...THE SELF-TOLERANT T CELL...ACCESS TO SELF-ANTIGEN/MHC...LYMPHOPENIA-INDUCED HOMEOSTATIC...A NOVEL ROLE FOR...CONCLUDING REMARKSNOTEREFERENCES |
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-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases J. Immunol. 155,1151-1164[Abstract]
