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Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis
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12 Simeonovic, C.J. et al. (1997) Eosinophils are not required for the rejection of neovascularized fetal pig proislet xenografts in mice. J. Immunol. 158, 2490–2499 13 Braun, M. et al. (2000) In the absence of CD8+ T cells, interleukin-5 and eosinophils promote the rejection of MHC class I- and II-disparate vascularized cardiac allograft. Eur. J. Immunol. 30, 1290–1296 14 Le Moine, A. et al. (1999) IL-5 mediates eosinophilic rejection of MHC class II-disparate skin allografts in mice. J. Immunol. 163, 3778–3784 15 Gleich, G.J. et al. (1993) The biology of the eosinophilic leukocyte. Annu. Rev. Med. 44, 85–101 16 Grunig, G. et al. (1998) Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 17 Schleimer, R.P. et al. (1992) Interleukin-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium: association with expression of VCAM-1. J. Immunol. 148, 1086–1092 18 Rothenberg, M.E. et al. (1995) Murine eotaxin: an eosinophil chemoattractant inducible in endothelial cells and in interleukin-4-induced tumor suppression. Proc. Natl. Acad. Sci. U. S. A. 92, 8960–8964 19 Collins, P.D. et al. (1995) Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J. Exp. Med. 182, 1169–1174 20 Dong, Q. et al. (1999) IL-9 induces chemokine expression in lung epithelial cells and baseline
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airway eosinophilia in transgenic mice. Eur. J. Immunol. 29, 2130–2139 Gounni, A.S. et al. (2000) Interleukin-9 enhances interleukin-5 receptor expression, differentiation, and survival of human eosinophils. Blood 96, 2163–2171 Suzuki, K. et al. (2000) Role of common cytokine receptor gamma chain- and Jak3-dependent signaling in the proliferation and survival of murine mast cells. Blood 96, 2172–2180 Marone, G. et al. (2000) Immunological interactions between human eosinophils and cardiac mast cells. In Human Eosinophils: Biological and Clinical Aspects (Chemical Immunology) (Vol. 76) (Marone, G. ed.), pp. 118–133, Karger Dubucquoi, S. et al. (1994) Interleukin 5 synthesis by eosinophils: association with granules and immunoglobulin-dependent secretion. J. Exp. Med. 179, 703–708 Wedemeyer, J. et al. (2000) Roles of mast cells and basophils in innate and acquired immunity. Curr. Opin. Immunol. 12, 624–631 Foucras, G. et al. (2000) Dendritic cells prime in vivo alloreactive CD4+ T lymphocytes toward type 2 cytokine- and TGF-β-producing cells in the absence of CD8+ T cell activation. J. Immunol. 165, 4994–5003 Noble, A. et al. (1998) Suppression of immune responses by CD8 cells. II. Qa-1 on activated B cells stimulates CD8 cell suppression of T helper 2 responses. J. Immunol. 160, 566–571
Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis Jörg J. Goronzy and Cornelia M. Weyand T-cell diversity is generated through the production of new thymic emigrants. Thymic function declines with age, and the T-cell pool is maintained through homeostatic proliferation of naive peripheral T cells. This article discusses the impact of thymic output and peripheral T-cell homeostasis on the development of rheumatoid arthritis (RA). It is proposed that thymic output is prematurely compromised in RA patients. A compensatory expansion of peripheral T cells results in a contracted and distorted repertoire, possibly favoring T cells with autoreactive potential. Increased risk of autoimmunity, as a consequence of abnormal T-cell population dynamics, could be a common mechanism in chronic inflammatory diseases.
Why does the risk of many diseases considered to have an autoimmune pathogenesis increase with age? Only a few autoimmune diseases, such as type 1 diabetes mellitus, are typical childhood
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28 Shustov, A. et al. (2000) Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity. J. Clin. Invest. 106, R39–R47 29 Paul, L.C. (1999) Chronic allograft nephropathy: an update. Kidney Int. 56, 783–793 30 Le Moine, A. et al. (1999) Critical roles for IL-4, IL-5 and eosinophils in chronic skin allograft rejection. J. Clin. Invest. 103, 1659–1667 31 Baetta, R. et al. (2000) Upregulation and activation of Stat6 precede vascular smooth muscle cell proliferation in carotid artery injury model. Arterioscler. Thromb. Vasc. Biol. 20, 931–939 32 Ensminger, S.M. et al. (2000) Intragraft interleukin-4 mRNA expression after short-term CD154 blockade may trigger delayed development of transplant arteriosclerosis in the absence of CD8+ T cells. Transplantation 70, 955–963 33 Nolan, C.R. et al. (1995) Role of the eosinophil in chronic vascular rejection of renal allografts. Am. J. Kidney Dis. 26, 634–642 34 Martinez, O.M. et al. (1993) Evidence for a nonclassical pathway of graft rejection involving interleukin 5 and eosinophils. Transplantation 55, 909–918 35 Youssem, S.A. (1992) Graft eosinophilia in lung transplantation. Hum. Pathol. 23, 1172–1177 36 Trull, A.K. et al. (2000) Randomized trial of blood eosinophil count monitoring as a guide to corticosteroid dosage adjustment after heart transplantation. Transplantation 70, 802–809
diseases; others, such as rheumatoid arthritis (RA), preferentially develop after the age of 50 years. The aging immune system undergoes drastic changes, of which thymic involution after puberty might be the most important. Recent experiments in mice suggest that the adult T-cell repertoire is not only influenced by thymic selection, but is modified by homeostatic proliferation of naive T cells. Peripheral self-replication has important implications for the maintenance of tolerance and, thus, could contribute to the development of autoimmune diseases. In this article, it is proposed that peripheral repertoire selection plays a key role in the pathogenesis of RA. Previous studies have postulated that the primary determinants of RA pathogenesis are defects in thymic selection, which are at least partly imposed by disease-associated MHC class II polymorphisms1–5. In the model proposed here, self-replication of naive T cells, which is accelerated to help compensate for reduced thymic output, leads to clonal expansion of cells with higher affinity to self at the expense of those that are weakly self-reactive. The resulting contraction in diversity increases the risk for autoimmune responses. Equally important, T cells that have undergone progressive self-replication acquire properties that are reminiscent of senescent cells; such cells have developed survival strategies and express effector functions that could be relevant for the disease manifestations of RA.
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Fig. 1. Reduced thymic output and enhanced peripheral T-cell turnover in rheumatoid arthritis (RA). The frequency of recent thymic emigrants can be estimated by quantifying T-cell receptor excision circles (TRECs) by competitive PCR. The length of telomeric DNA can provide information about the replicative history of peripheral lymphocytes. With normal physiological aging (red), thymic output declines and telomeric ends are shortened. In patients with RA (blue), reduction of thymic emigrants and erosion of T-cell telomeres occur prematurely by ~20 years, suggesting impairment of thymic function and acceleration of peripheral T-cell turnover. Telomere length (a) and TRECs (b) of peripheral CD4+ T cells are shown as regression curves based on published data17.
T-cell generation: thymic production versus homeostatic proliferation
Jörg J. Goronzy* Cornelia M. Weyand Depts of Medicine and Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. *e-mail: goronzy.jorg@ mayo.edu
Mature T cells that express αβ T-cell receptors (TCRs) are generated in the thymus and are selected through the processes of positive and negative selection. Because positive selection is dependent on the recognition of self-peptides complexed with self-MHC, T-cell recognition is inevitably associated with recognition of self. Thymic T-cell output dramatically decreases after puberty, and it is not known to what degree it contributes to T-cell replenishment during adult life6. During adulthood, the size of the peripheral T-cell pool is maintained, possibly with homeostatic proliferation as the dominant mechanism. Recent studies estimating thymic production in humans have made use of TCR excision circles (TRECs) produced during TCR rearrangement. Formation of a productive TCRα gene requires deletion of the TCRγ gene, which is positioned in the TCRα locus. The deleted TCRγ gene remains present as an extrachromosomal DNA circle that is http://immunology.trends.com
probably progressively lost with time7. The TRECs are episomal, do not replicate and are, therefore, diluted with cell division. The number of TREC-containing cells declines by nearly two logs between the ages of 20 and 65 years. Persistence of small numbers of TRECs could indicate some basal thymic function with advancing age. Indeed, increases in TREC numbers have been found in some middle-aged individuals after lymphocyte depletion8,9. However, in general, TREC numbers are exceedingly small with advancing age, suggesting that thymic production is unable to meet the demand for peripheral T-cell replenishment. The demand for replenishment in the T-cell system is enormous; the estimates range from 2 × 109 to 4 × 109 cells per day in human in vivo studies10. Turnover is higher in memory T cells in comparison with naive cells, but naive cells also have a finite lifespan and proliferate to compensate for natural attrition, cell death and transition into the memory compartment. After puberty, the size of the memory T-cell population increases with age but at only marginal expense to the naive compartment, suggesting that naive and memory cells do not compete for the same space. Similar conclusions have been reached from murine adoptive transfer studies11. Studies of naive T-cell homeostasis in mice were initially difficult because the lifespan of naive T cells is substantial in comparison with the lifespan of the murine host, and naive cells were thought to survive in a quiescent state without stimulation of the TCR. More-recent studies have challenged this view and have demonstrated that prolonged survival of naive T cells is dependent on the recognition of self-antigen11. The importance of selfrecognition in peripheral T-cell homeostasis is more evident in mice in which the T-cell compartment has been artificially reduced12–14. Under such circumstances, naive T cells proliferate to fill the unoccupied space and do so while maintaining a predominantly naive phenotype and without gaining effector functions. Significantly, proliferation is dependent on the same MHC and peptide ligands that have led to positive selection in the thymus. These data introduced the concept that peripheral self-recognition modifies the thymically selected repertoire. These selection mechanisms are important for normal T-cell homeostasis but probably gain particular relevance in the aged individual or in the T-cell-deficient host15. Thymic activity and self-replication in RA
Evidence that T-cell generation might not be intact in patients with RA initially came from therapeutic intervention studies involving T-cell depletion. Patients who were treated with T-cell-depleting monoclonal antibodies developed profound and longstanding lymphopenia. Many patients had very limited ability to generate new naive T cells, and the repertoire of T cells filling the space was severely
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contracted16. In spite of this extended lymphopenia, the clinical benefits were only temporary, suggesting that this contracted repertoire was sufficient to maintain the disease. Naturally, most of these patients were of age 40 years and older and it was, therefore, not clear whether age or the disease was the more confounding variable in influencing T-cell generation. The question of whether mechanisms of T-cell generation are intact and age-appropriate was addressed in a recent study in which TREC numbers in peripheral CD4+ T cells of patients with RA and healthy individuals were compared17. TREC levels in patients with RA were threefold less than in age-matched controls (Fig. 1). There are two possible explanations for this finding. RA patients could undergo increased T-cell turnover as part of the inflammatory disease, leading to a dilution of TREC+ cells. This mechanism has been implicated in the TREC reduction observed in patients with HIV (Ref. 18). Alternatively, patients with RA might have reduced thymic activity. Support for inadequate thymic output as the underlying defect came from the observation that the decrease in TRECs could not be attributed to an increase in the size of the memory compartment. TREC concentrations were already reduced in 20–30-year-old patients. After age 25, RA patients and healthy controls had similar exponential declines in TRECs of 0.34/year and 0.35/year, respectively, suggesting that TREC reduction had occurred early in life and that patients did not have an increased turnover of naive T cells that would lead to progressive TREC dilution. Indeed, the number of T cells in the cell cycle in patients with RA is reduced and not increased (J.J. Goronzy, unpublished). A primary defect in thymic T-cell generation in RA patients would have to be compensated for by increased self-replication of peripheral T cells. Similarly, increased replicative history of peripheral T cells would also be expected if the premature disappearance of TREC+CD4+ T cells were a reflection of excessive T-cell proliferation in the periphery. Indeed, experimental studies demonstrate that T cells in patients with RA have replicated much more than expected for the patient’s age. Weng et al. have described an erosion of the telomeric reserve in peripheral T cells with increasing age19. They reported that telomeres are shorter in memory than in naive T cells; however, both subpopulations also had progressive telomeric loss with age, indicating self-replication. In RA patients, the telomeric reserve is already exhausted at age 20–30 years with no further age-dependent decline17. Naive T cells are more affected by ageinappropriate telomeric erosion than are memory T cells. In fact, telomeres from naive CD4+ T cells from patients with RA are as short as telomeres from memory T cells of healthy controls. http://immunology.trends.com
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Fig. 2. Abnormal T-cell population dynamics in rheumatoid arthritis (RA). T-cell diversity is generated through the production of new T cells in the thymus and is maintained through homeostatic proliferation of peripheral T cells. Central and peripheral selection is controlled by the recognition of self-antigens. The schematic diagram illustrates how repertoire selection might be abnormal in patients with RA. Individuals who develop RA undergo a decline in thymic function during early adolescence, inducing a temporary increase in homeostatic proliferation. Because autoproliferation is driven by the recognition of self-antigen, the resulting repertoire is contracted and biased towards the recognition of self. Repertoire contraction progresses with age, paralleled by an increasing risk of developing disease.
T-cell repertoire contraction and oligoclonality in RA
Homeostatic proliferation is dependent on TCR triggering. In the T-cell-depleted mouse, the turnover time of adoptively transferred T cells depends on the affinity of the TCR–ligand interaction. TCRs that have passed thymic selection represent a continuum of affinities for complexes of self-peptide with self-MHC (Refs 14,15). Naive T cells expressing low-affinity receptors for selfantigens fill the compartment more slowly than do adoptively transferred T cells that recognize selfpeptides with higher affinity13. Increased homeostatic proliferation to fill the space might, therefore, lead to competitive exclusion of TCRs and, ultimately, to contraction of the repertoire. Recent studies have estimated the global diversity of the human T-cell repertoire. Arstila and colleagues used a random sequencing approach that provided a minimal estimate of 106 TCR β-chains within the total compartment of 1011 T cells20. Wagner et al. used a limiting dilution approach that established an upper estimate of 107 different TCR β-chains21. In the compartment of naive T cells, each TCR β-chain is combined with approximately 100 different α-chains, suggesting that total T-cell diversity is of the order of 108–109 T cells. The diversity of the memory repertoire is significantly contracted and contains ten-times fewer TCR β-chains, each of which is combined with only one particular α-chain, indicating that 99% of T-cell diversity is contributed by the naive compartment.
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increased oligoclonality are all reminiscent of changes typically occurring in the elderly, suggesting that patients with RA undergo a premature aging of the T-cell system.
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Fig. 3. Immunosenescent CD4+ T cells with antigen-presenting cells (APCs). Following excessive replication, CD4+ T cells lose expression of CD28 and CD40 ligand (L) and are no longer under the control of these costimulatory pathways. They acquire regulatory molecules generally expressed on natural killer (NK) cells such as CD158 killer-cell inhibitory receptors (KIR) and CD161. In parallel, they change their functional profile so that they are able to produce large amounts of interferon γ (IFN-γ) and to kill through the granzyme/perforin pathway. Abbreviation: TCR, T-cell receptor.
In RA patients, the repertoires of both naive and memory T cells are contracted. The median TCR β-chain frequencies in the peripheral blood of patients with RA were approximately tenfold higher than in controls. Naive T cells had a higher diversity than memory T cells; however, most of these naive T cells were the result of clonal expansions, and infrequent T cells were the rare exception, in contrast to the repertoire in healthy control individuals. If clonal contraction is driven by the recognition of self-antigen, as one would expect from the murine models of homeostatic proliferation, then the contracted repertoire in RA should be biased towards a higher affinity recognition of self (Fig. 2). This is difficult to test for naive T cells, but there is evidence that this might occur in the memory compartment in patients with RA. Patients with RA frequently harbor CD4+ and CD8+ T-cell clones in the periphery. These T-cell clonotypes have reached such a large clonal size that they can be detected by flow cytometric analysis, by TCR restriction fragment length polymorphism (TCR-RFLP) analysis, or by TCR spectrotyping22,23. Considering the profound reduction in T-cell diversity, these clones do not represent isolated expansions but, rather, reflect a general contraction in the repertoire. These clones are responsive to self-antigens; for one of these clones, the antigenic peptide has been identified as an HLA-DQ-derived peptide23,24. Similar clonal expansions, in particular of CD8+ T cells, are also found in some elderly individuals25,26. Reduction of TRECs, telomere shortening of T cells and http://immunology.trends.com
How can T-cell repertoire contraction and premature senescence translate into disease mechanisms operational in RA and possibly other autoimmune diseases? It is currently unclear how repertoire contraction could affect peripheral tolerance mechanisms. Peripheral tolerance is regulated by a variety of mechanisms at the singlecell level, but additional factors, such as a critical density of activated cells and competition for available space, are important variables of peripheral control mechanisms, such as clonal ignorance. In this context, the diversity of the population and the clonal sizes of its members probably determine whether an immune response is aborted or sustained. Equally important, premature senescence is associated with a shift in the functional profile of peripheral lymphocytes (Fig. 3). With replicative senescence, CD8+ T cells and, to a lesser extent, CD4+ T cells lose the expression of CD28 and gain independence of the regulatory control brought about by CD80 and CD86 (Ref. 27). CD4+CD28null T cells are
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Fig. 4. A model of repertoire selection in rheumatoid arthritis (RA). Individuals who develop RA go through a stage of accelerated selfreplication of peripheral T cells, which partly compensates for a premature decline in thymic output. With peripheral selection being prominent, the T-cell repertoire loses diversity and is biased towards autoreactivity. The disease reflects a breakdown in tolerance to common antigens that are preferentially recognized in the synovium1,2,5,23,24. In addition, T-cell effector functions acquired with premature senescence are crucial in shaping the disease manifestations. Such a disease model does not need to be specific to RA, but could also apply to other autoimmune diseases.
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functionally competent and have gained several important properties. They have an increased resistance to apoptosis-inducing stimuli, in particular Fas stimulation. They have acquired several natural killer (NK)-cell-type features, including the expression of MHC class I-recognizing receptors and the acquisition of cytotoxic abilities through the perforin/granzyme B pathways28,29. These effector functions are a foreboding prognostic indicator of joint destruction in the synovial inflammation, and they also contribute to the extra-articular manifestations of RA, including the neutropenia that is characteristic of Felty’s syndrome and the increased vascular morbidity in RA (Refs 30–33). Concluding remarks
Acknowledgements This work was supported by the National Institutes of Health grants RO1 AR41974, RO1 AG15043 and R21 GM58604 (J.J.G.), and RO1 AR42527 and AI44142 (C.M.W.).
Recent evidence suggests that peripheral T-cell homeostasis is maintained through the replication of naive T cells that recognize self-antigens. Peripheral positive selection is particularly important in the T-cell-deficient host, such as in the aged individual who has minimal thymic function. This article proposes that abnormalities in T-cell population dynamics have relevance for disease, particularly RA, because patients affected by this
References 1 Albani, S. et al. (1995) Positive selection in autoimmunity: abnormal immune responses to a bacterial dnaJ antigenic determinant in patients with early rheumatoid arthritis. Nat. Med. 1, 448–452 2 Albani, S. et al. (1996) A multistep molecular mimicry hypothesis for the pathogenesis of rheumatoid arthritis. Immunol. Today 17, 466–470 3 Walser-Kuntz, D.R. et al. (1995) Mechanisms underlying the formation of the T cell receptor repertoire in rheumatoid arthritis. Immunity 2, 597–605 4 Nepom, G.T. (1998) Major histocompatibility complex-directed susceptibility to rheumatoid arthritis. Adv. Immunol. 68, 315–332 5 Kouskoff, V. et al. (1996) Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 6 Haynes, B.F. et al. (1999) Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection. J. Clin. Invest. 103, 453–460 7 Kong, F.K. et al. (1999) T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc. Natl. Acad. Sci. U. S. A. 96, 1536–1540 8 Jamieson, B.D. et al. (1999) Generation of functional thymocytes in the human adult. Immunity 10, 569–575 9 Douek, D.C. et al. (2000) Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355, 1875–1881 10 Hellerstein, M.K. (1999) Measurement of T-cell kinetics: recent methodologic advances. Immunol. Today 20, 438–441 11 Freitas, A.A. et al. (2000) Population biology of lymphocytes: the flight for survival. Annu. Rev. Immunol. 18, 83–111 12 Ernst, B. et al. (1999) The peptide ligands mediating positive selection in the thymus http://immunology.trends.com
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syndrome have an age-inappropriate and premature decline in thymic output. Emerging data support the hypothesis that compensatory proliferation and peripheral selection of naive T cells eventually produces a profoundly abnormal T-cell repertoire biased towards autorecognition (Fig. 4). Excessive proliferation of surviving T cells, driven by the need to fill the void, inevitably generates senescent T cells that lose certain functional capabilities and gain others that have potential for tissue injury. It is well known that, although immunosuppressive measures are able to control the disease activity of RA, they consistently fail to induce remission. In particular, therapies based on depletion of CD4+ T cells have not yielded any lasting benefit. This is to be expected if the T-cell repertoire is contracted and clonally expanded and the ability of de novo thymic T-cell generation is compromised. Therefore, bone-marrow transplantation, currently advocated for autoimmune diseases, might not be efficacious and could lead to increased morbidity in patients with RA. Our model would predict that the future treatment of RA should shift focus from primary immunosuppression to novel measures of immunoreconstitution.
control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 Goldrath, A.W. et al. (1999) Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183–190 Viret, C. et al. (1999) Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition. Immunity 10, 559–568 Goldrath, A.W. et al. (1999) Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 Jendro, M.C. et al. (1995) Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis. Arthritis Rheum. 38, 1242–1251 Koetz, K. et al. (2000) T cell homeostasis in patients with rheumatoid arthritis. Proc. Natl. Acad. Sci. U. S. A. 97, 9203–9208 Hazenberg, M.D. et al. (2000) Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat. Med. 6, 1036–1042 Weng, N.P. et al. (1995) Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc. Natl. Acad. Sci. U. S. A. 92, 11091–11094 Arstila, T.P. et al. (1999) A direct estimate of the human αβ T cell receptor diversity. Science 286, 958–961 Wagner, U.G. et al. (1998) Perturbation of the T cell repertoire in rheumatoid arthritis. Proc. Natl. Acad. Sci. U. S. A. 95, 14447–14452 DerSimonian, H. et al. (1993) Clonal V alpha 12.1+ T cell expansions in the peripheral blood of rheumatoid arthritis patients. J. Exp. Med. 177, 1623–1631 Schmidt, D. et al. (1996) CD4+ CD7− CD28− T cells are expanded in rheumatoid arthritis and
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are characterized by autoreactivity. J. Clin. Invest. 97, 2027–2037 Behar, S.M. et al. (1998) Clonally expanded V alpha 12+ (AV12S1),CD8+ T cells from a patient with rheumatoid arthritis are autoreactive. Arthritis Rheum. 41, 498–506 Ku, C.C. et al. (1997) CD8+ T-cell clones in old mice. Immunol Rev. 160, 139–144 Posnett, D.N. et al. (1994) Clonal populations of T cells in normal elderly humans: the T cell equivalent to ‘benign monoclonal gammapathy’. J. Exp. Med. 179, 609–618 Vallejo, A.N. et al. (1998) Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity. J. Biol. Chem. 273, 8119–8129 Namekawa, T. et al. (2000) Killer cell activating receptors function as costimulatory molecules on CD4+CD28null T cells clonally expanded in rheumatoid arthritis. J. Immunol. 165, 1138–1145 Warrington, K. et al. CD4+CD28null T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. Arthritis Rheum. (in press) Martens, P.B. et al. (1997) Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum. 40, 1106–1114 Pasceri, V. et al. (1999) A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation 100, 2124–2126 Coakley, G. et al. (2000) CD8+ CD57+ T cells from healthy elderly subjects suppress neutrophil development in vitro: implications for the neutropenia of Felty’s and large granular lymphocyte syndromes. Arthritis Rheum. 43, 834–843 Liuzzo, G. et al. (2000) Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 101, 2883–2888
12 Simeonovic, C.J. et al. (1997) Eosinophils are not required for the rejection of neovascularized fetal pig proislet xenografts in mice. J. Immunol. 158, 2490–2499 13 Braun, M. et al. (2000) In the absence of CD8+ T cells, interleukin-5 and eosinophils promote the rejection of MHC class I- and II-disparate vascularized cardiac allograft. Eur. J. Immunol. 30, 1290–1296 14 Le Moine, A. et al. (1999) IL-5 mediates eosinophilic rejection of MHC class II-disparate skin allografts in mice. J. Immunol. 163, 3778–3784 15 Gleich, G.J. et al. (1993) The biology of the eosinophilic leukocyte. Annu. Rev. Med. 44, 85–101 16 Grunig, G. et al. (1998) Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 17 Schleimer, R.P. et al. (1992) Interleukin-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium: association with expression of VCAM-1. J. Immunol. 148, 1086–1092 18 Rothenberg, M.E. et al. (1995) Murine eotaxin: an eosinophil chemoattractant inducible in endothelial cells and in interleukin-4-induced tumor suppression. Proc. Natl. Acad. Sci. U. S. A. 92, 8960–8964 19 Collins, P.D. et al. (1995) Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J. Exp. Med. 182, 1169–1174 20 Dong, Q. et al. (1999) IL-9 induces chemokine expression in lung epithelial cells and baseline
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airway eosinophilia in transgenic mice. Eur. J. Immunol. 29, 2130–2139 Gounni, A.S. et al. (2000) Interleukin-9 enhances interleukin-5 receptor expression, differentiation, and survival of human eosinophils. Blood 96, 2163–2171 Suzuki, K. et al. (2000) Role of common cytokine receptor gamma chain- and Jak3-dependent signaling in the proliferation and survival of murine mast cells. Blood 96, 2172–2180 Marone, G. et al. (2000) Immunological interactions between human eosinophils and cardiac mast cells. In Human Eosinophils: Biological and Clinical Aspects (Chemical Immunology) (Vol. 76) (Marone, G. ed.), pp. 118–133, Karger Dubucquoi, S. et al. (1994) Interleukin 5 synthesis by eosinophils: association with granules and immunoglobulin-dependent secretion. J. Exp. Med. 179, 703–708 Wedemeyer, J. et al. (2000) Roles of mast cells and basophils in innate and acquired immunity. Curr. Opin. Immunol. 12, 624–631 Foucras, G. et al. (2000) Dendritic cells prime in vivo alloreactive CD4+ T lymphocytes toward type 2 cytokine- and TGF-β-producing cells in the absence of CD8+ T cell activation. J. Immunol. 165, 4994–5003 Noble, A. et al. (1998) Suppression of immune responses by CD8 cells. II. Qa-1 on activated B cells stimulates CD8 cell suppression of T helper 2 responses. J. Immunol. 160, 566–571
Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis Jörg J. Goronzy and Cornelia M. Weyand T-cell diversity is generated through the production of new thymic emigrants. Thymic function declines with age, and the T-cell pool is maintained through homeostatic proliferation of naive peripheral T cells. This article discusses the impact of thymic output and peripheral T-cell homeostasis on the development of rheumatoid arthritis (RA). It is proposed that thymic output is prematurely compromised in RA patients. A compensatory expansion of peripheral T cells results in a contracted and distorted repertoire, possibly favoring T cells with autoreactive potential. Increased risk of autoimmunity, as a consequence of abnormal T-cell population dynamics, could be a common mechanism in chronic inflammatory diseases.
Why does the risk of many diseases considered to have an autoimmune pathogenesis increase with age? Only a few autoimmune diseases, such as type 1 diabetes mellitus, are typical childhood
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28 Shustov, A. et al. (2000) Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity. J. Clin. Invest. 106, R39–R47 29 Paul, L.C. (1999) Chronic allograft nephropathy: an update. Kidney Int. 56, 783–793 30 Le Moine, A. et al. (1999) Critical roles for IL-4, IL-5 and eosinophils in chronic skin allograft rejection. J. Clin. Invest. 103, 1659–1667 31 Baetta, R. et al. (2000) Upregulation and activation of Stat6 precede vascular smooth muscle cell proliferation in carotid artery injury model. Arterioscler. Thromb. Vasc. Biol. 20, 931–939 32 Ensminger, S.M. et al. (2000) Intragraft interleukin-4 mRNA expression after short-term CD154 blockade may trigger delayed development of transplant arteriosclerosis in the absence of CD8+ T cells. Transplantation 70, 955–963 33 Nolan, C.R. et al. (1995) Role of the eosinophil in chronic vascular rejection of renal allografts. Am. J. Kidney Dis. 26, 634–642 34 Martinez, O.M. et al. (1993) Evidence for a nonclassical pathway of graft rejection involving interleukin 5 and eosinophils. Transplantation 55, 909–918 35 Youssem, S.A. (1992) Graft eosinophilia in lung transplantation. Hum. Pathol. 23, 1172–1177 36 Trull, A.K. et al. (2000) Randomized trial of blood eosinophil count monitoring as a guide to corticosteroid dosage adjustment after heart transplantation. Transplantation 70, 802–809
diseases; others, such as rheumatoid arthritis (RA), preferentially develop after the age of 50 years. The aging immune system undergoes drastic changes, of which thymic involution after puberty might be the most important. Recent experiments in mice suggest that the adult T-cell repertoire is not only influenced by thymic selection, but is modified by homeostatic proliferation of naive T cells. Peripheral self-replication has important implications for the maintenance of tolerance and, thus, could contribute to the development of autoimmune diseases. In this article, it is proposed that peripheral repertoire selection plays a key role in the pathogenesis of RA. Previous studies have postulated that the primary determinants of RA pathogenesis are defects in thymic selection, which are at least partly imposed by disease-associated MHC class II polymorphisms1–5. In the model proposed here, self-replication of naive T cells, which is accelerated to help compensate for reduced thymic output, leads to clonal expansion of cells with higher affinity to self at the expense of those that are weakly self-reactive. The resulting contraction in diversity increases the risk for autoimmune responses. Equally important, T cells that have undergone progressive self-replication acquire properties that are reminiscent of senescent cells; such cells have developed survival strategies and express effector functions that could be relevant for the disease manifestations of RA.
http://immunology.trends.com 1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(00)01841-X
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Fig. 1. Reduced thymic output and enhanced peripheral T-cell turnover in rheumatoid arthritis (RA). The frequency of recent thymic emigrants can be estimated by quantifying T-cell receptor excision circles (TRECs) by competitive PCR. The length of telomeric DNA can provide information about the replicative history of peripheral lymphocytes. With normal physiological aging (red), thymic output declines and telomeric ends are shortened. In patients with RA (blue), reduction of thymic emigrants and erosion of T-cell telomeres occur prematurely by ~20 years, suggesting impairment of thymic function and acceleration of peripheral T-cell turnover. Telomere length (a) and TRECs (b) of peripheral CD4+ T cells are shown as regression curves based on published data17.
T-cell generation: thymic production versus homeostatic proliferation
Jörg J. Goronzy* Cornelia M. Weyand Depts of Medicine and Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. *e-mail: goronzy.jorg@ mayo.edu
Mature T cells that express αβ T-cell receptors (TCRs) are generated in the thymus and are selected through the processes of positive and negative selection. Because positive selection is dependent on the recognition of self-peptides complexed with self-MHC, T-cell recognition is inevitably associated with recognition of self. Thymic T-cell output dramatically decreases after puberty, and it is not known to what degree it contributes to T-cell replenishment during adult life6. During adulthood, the size of the peripheral T-cell pool is maintained, possibly with homeostatic proliferation as the dominant mechanism. Recent studies estimating thymic production in humans have made use of TCR excision circles (TRECs) produced during TCR rearrangement. Formation of a productive TCRα gene requires deletion of the TCRγ gene, which is positioned in the TCRα locus. The deleted TCRγ gene remains present as an extrachromosomal DNA circle that is http://immunology.trends.com
probably progressively lost with time7. The TRECs are episomal, do not replicate and are, therefore, diluted with cell division. The number of TREC-containing cells declines by nearly two logs between the ages of 20 and 65 years. Persistence of small numbers of TRECs could indicate some basal thymic function with advancing age. Indeed, increases in TREC numbers have been found in some middle-aged individuals after lymphocyte depletion8,9. However, in general, TREC numbers are exceedingly small with advancing age, suggesting that thymic production is unable to meet the demand for peripheral T-cell replenishment. The demand for replenishment in the T-cell system is enormous; the estimates range from 2 × 109 to 4 × 109 cells per day in human in vivo studies10. Turnover is higher in memory T cells in comparison with naive cells, but naive cells also have a finite lifespan and proliferate to compensate for natural attrition, cell death and transition into the memory compartment. After puberty, the size of the memory T-cell population increases with age but at only marginal expense to the naive compartment, suggesting that naive and memory cells do not compete for the same space. Similar conclusions have been reached from murine adoptive transfer studies11. Studies of naive T-cell homeostasis in mice were initially difficult because the lifespan of naive T cells is substantial in comparison with the lifespan of the murine host, and naive cells were thought to survive in a quiescent state without stimulation of the TCR. More-recent studies have challenged this view and have demonstrated that prolonged survival of naive T cells is dependent on the recognition of self-antigen11. The importance of selfrecognition in peripheral T-cell homeostasis is more evident in mice in which the T-cell compartment has been artificially reduced12–14. Under such circumstances, naive T cells proliferate to fill the unoccupied space and do so while maintaining a predominantly naive phenotype and without gaining effector functions. Significantly, proliferation is dependent on the same MHC and peptide ligands that have led to positive selection in the thymus. These data introduced the concept that peripheral self-recognition modifies the thymically selected repertoire. These selection mechanisms are important for normal T-cell homeostasis but probably gain particular relevance in the aged individual or in the T-cell-deficient host15. Thymic activity and self-replication in RA
Evidence that T-cell generation might not be intact in patients with RA initially came from therapeutic intervention studies involving T-cell depletion. Patients who were treated with T-cell-depleting monoclonal antibodies developed profound and longstanding lymphopenia. Many patients had very limited ability to generate new naive T cells, and the repertoire of T cells filling the space was severely
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contracted16. In spite of this extended lymphopenia, the clinical benefits were only temporary, suggesting that this contracted repertoire was sufficient to maintain the disease. Naturally, most of these patients were of age 40 years and older and it was, therefore, not clear whether age or the disease was the more confounding variable in influencing T-cell generation. The question of whether mechanisms of T-cell generation are intact and age-appropriate was addressed in a recent study in which TREC numbers in peripheral CD4+ T cells of patients with RA and healthy individuals were compared17. TREC levels in patients with RA were threefold less than in age-matched controls (Fig. 1). There are two possible explanations for this finding. RA patients could undergo increased T-cell turnover as part of the inflammatory disease, leading to a dilution of TREC+ cells. This mechanism has been implicated in the TREC reduction observed in patients with HIV (Ref. 18). Alternatively, patients with RA might have reduced thymic activity. Support for inadequate thymic output as the underlying defect came from the observation that the decrease in TRECs could not be attributed to an increase in the size of the memory compartment. TREC concentrations were already reduced in 20–30-year-old patients. After age 25, RA patients and healthy controls had similar exponential declines in TRECs of 0.34/year and 0.35/year, respectively, suggesting that TREC reduction had occurred early in life and that patients did not have an increased turnover of naive T cells that would lead to progressive TREC dilution. Indeed, the number of T cells in the cell cycle in patients with RA is reduced and not increased (J.J. Goronzy, unpublished). A primary defect in thymic T-cell generation in RA patients would have to be compensated for by increased self-replication of peripheral T cells. Similarly, increased replicative history of peripheral T cells would also be expected if the premature disappearance of TREC+CD4+ T cells were a reflection of excessive T-cell proliferation in the periphery. Indeed, experimental studies demonstrate that T cells in patients with RA have replicated much more than expected for the patient’s age. Weng et al. have described an erosion of the telomeric reserve in peripheral T cells with increasing age19. They reported that telomeres are shorter in memory than in naive T cells; however, both subpopulations also had progressive telomeric loss with age, indicating self-replication. In RA patients, the telomeric reserve is already exhausted at age 20–30 years with no further age-dependent decline17. Naive T cells are more affected by ageinappropriate telomeric erosion than are memory T cells. In fact, telomeres from naive CD4+ T cells from patients with RA are as short as telomeres from memory T cells of healthy controls. http://immunology.trends.com
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Fig. 2. Abnormal T-cell population dynamics in rheumatoid arthritis (RA). T-cell diversity is generated through the production of new T cells in the thymus and is maintained through homeostatic proliferation of peripheral T cells. Central and peripheral selection is controlled by the recognition of self-antigens. The schematic diagram illustrates how repertoire selection might be abnormal in patients with RA. Individuals who develop RA undergo a decline in thymic function during early adolescence, inducing a temporary increase in homeostatic proliferation. Because autoproliferation is driven by the recognition of self-antigen, the resulting repertoire is contracted and biased towards the recognition of self. Repertoire contraction progresses with age, paralleled by an increasing risk of developing disease.
T-cell repertoire contraction and oligoclonality in RA
Homeostatic proliferation is dependent on TCR triggering. In the T-cell-depleted mouse, the turnover time of adoptively transferred T cells depends on the affinity of the TCR–ligand interaction. TCRs that have passed thymic selection represent a continuum of affinities for complexes of self-peptide with self-MHC (Refs 14,15). Naive T cells expressing low-affinity receptors for selfantigens fill the compartment more slowly than do adoptively transferred T cells that recognize selfpeptides with higher affinity13. Increased homeostatic proliferation to fill the space might, therefore, lead to competitive exclusion of TCRs and, ultimately, to contraction of the repertoire. Recent studies have estimated the global diversity of the human T-cell repertoire. Arstila and colleagues used a random sequencing approach that provided a minimal estimate of 106 TCR β-chains within the total compartment of 1011 T cells20. Wagner et al. used a limiting dilution approach that established an upper estimate of 107 different TCR β-chains21. In the compartment of naive T cells, each TCR β-chain is combined with approximately 100 different α-chains, suggesting that total T-cell diversity is of the order of 108–109 T cells. The diversity of the memory repertoire is significantly contracted and contains ten-times fewer TCR β-chains, each of which is combined with only one particular α-chain, indicating that 99% of T-cell diversity is contributed by the naive compartment.
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increased oligoclonality are all reminiscent of changes typically occurring in the elderly, suggesting that patients with RA undergo a premature aging of the T-cell system.
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Fig. 3. Immunosenescent CD4+ T cells with antigen-presenting cells (APCs). Following excessive replication, CD4+ T cells lose expression of CD28 and CD40 ligand (L) and are no longer under the control of these costimulatory pathways. They acquire regulatory molecules generally expressed on natural killer (NK) cells such as CD158 killer-cell inhibitory receptors (KIR) and CD161. In parallel, they change their functional profile so that they are able to produce large amounts of interferon γ (IFN-γ) and to kill through the granzyme/perforin pathway. Abbreviation: TCR, T-cell receptor.
In RA patients, the repertoires of both naive and memory T cells are contracted. The median TCR β-chain frequencies in the peripheral blood of patients with RA were approximately tenfold higher than in controls. Naive T cells had a higher diversity than memory T cells; however, most of these naive T cells were the result of clonal expansions, and infrequent T cells were the rare exception, in contrast to the repertoire in healthy control individuals. If clonal contraction is driven by the recognition of self-antigen, as one would expect from the murine models of homeostatic proliferation, then the contracted repertoire in RA should be biased towards a higher affinity recognition of self (Fig. 2). This is difficult to test for naive T cells, but there is evidence that this might occur in the memory compartment in patients with RA. Patients with RA frequently harbor CD4+ and CD8+ T-cell clones in the periphery. These T-cell clonotypes have reached such a large clonal size that they can be detected by flow cytometric analysis, by TCR restriction fragment length polymorphism (TCR-RFLP) analysis, or by TCR spectrotyping22,23. Considering the profound reduction in T-cell diversity, these clones do not represent isolated expansions but, rather, reflect a general contraction in the repertoire. These clones are responsive to self-antigens; for one of these clones, the antigenic peptide has been identified as an HLA-DQ-derived peptide23,24. Similar clonal expansions, in particular of CD8+ T cells, are also found in some elderly individuals25,26. Reduction of TRECs, telomere shortening of T cells and http://immunology.trends.com
How can T-cell repertoire contraction and premature senescence translate into disease mechanisms operational in RA and possibly other autoimmune diseases? It is currently unclear how repertoire contraction could affect peripheral tolerance mechanisms. Peripheral tolerance is regulated by a variety of mechanisms at the singlecell level, but additional factors, such as a critical density of activated cells and competition for available space, are important variables of peripheral control mechanisms, such as clonal ignorance. In this context, the diversity of the population and the clonal sizes of its members probably determine whether an immune response is aborted or sustained. Equally important, premature senescence is associated with a shift in the functional profile of peripheral lymphocytes (Fig. 3). With replicative senescence, CD8+ T cells and, to a lesser extent, CD4+ T cells lose the expression of CD28 and gain independence of the regulatory control brought about by CD80 and CD86 (Ref. 27). CD4+CD28null T cells are
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Fig. 4. A model of repertoire selection in rheumatoid arthritis (RA). Individuals who develop RA go through a stage of accelerated selfreplication of peripheral T cells, which partly compensates for a premature decline in thymic output. With peripheral selection being prominent, the T-cell repertoire loses diversity and is biased towards autoreactivity. The disease reflects a breakdown in tolerance to common antigens that are preferentially recognized in the synovium1,2,5,23,24. In addition, T-cell effector functions acquired with premature senescence are crucial in shaping the disease manifestations. Such a disease model does not need to be specific to RA, but could also apply to other autoimmune diseases.
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functionally competent and have gained several important properties. They have an increased resistance to apoptosis-inducing stimuli, in particular Fas stimulation. They have acquired several natural killer (NK)-cell-type features, including the expression of MHC class I-recognizing receptors and the acquisition of cytotoxic abilities through the perforin/granzyme B pathways28,29. These effector functions are a foreboding prognostic indicator of joint destruction in the synovial inflammation, and they also contribute to the extra-articular manifestations of RA, including the neutropenia that is characteristic of Felty’s syndrome and the increased vascular morbidity in RA (Refs 30–33). Concluding remarks
Acknowledgements This work was supported by the National Institutes of Health grants RO1 AR41974, RO1 AG15043 and R21 GM58604 (J.J.G.), and RO1 AR42527 and AI44142 (C.M.W.).
Recent evidence suggests that peripheral T-cell homeostasis is maintained through the replication of naive T cells that recognize self-antigens. Peripheral positive selection is particularly important in the T-cell-deficient host, such as in the aged individual who has minimal thymic function. This article proposes that abnormalities in T-cell population dynamics have relevance for disease, particularly RA, because patients affected by this
References 1 Albani, S. et al. (1995) Positive selection in autoimmunity: abnormal immune responses to a bacterial dnaJ antigenic determinant in patients with early rheumatoid arthritis. Nat. Med. 1, 448–452 2 Albani, S. et al. (1996) A multistep molecular mimicry hypothesis for the pathogenesis of rheumatoid arthritis. Immunol. Today 17, 466–470 3 Walser-Kuntz, D.R. et al. (1995) Mechanisms underlying the formation of the T cell receptor repertoire in rheumatoid arthritis. Immunity 2, 597–605 4 Nepom, G.T. (1998) Major histocompatibility complex-directed susceptibility to rheumatoid arthritis. Adv. Immunol. 68, 315–332 5 Kouskoff, V. et al. (1996) Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 6 Haynes, B.F. et al. (1999) Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection. J. Clin. Invest. 103, 453–460 7 Kong, F.K. et al. (1999) T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc. Natl. Acad. Sci. U. S. A. 96, 1536–1540 8 Jamieson, B.D. et al. (1999) Generation of functional thymocytes in the human adult. Immunity 10, 569–575 9 Douek, D.C. et al. (2000) Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355, 1875–1881 10 Hellerstein, M.K. (1999) Measurement of T-cell kinetics: recent methodologic advances. Immunol. Today 20, 438–441 11 Freitas, A.A. et al. (2000) Population biology of lymphocytes: the flight for survival. Annu. Rev. Immunol. 18, 83–111 12 Ernst, B. et al. (1999) The peptide ligands mediating positive selection in the thymus http://immunology.trends.com
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syndrome have an age-inappropriate and premature decline in thymic output. Emerging data support the hypothesis that compensatory proliferation and peripheral selection of naive T cells eventually produces a profoundly abnormal T-cell repertoire biased towards autorecognition (Fig. 4). Excessive proliferation of surviving T cells, driven by the need to fill the void, inevitably generates senescent T cells that lose certain functional capabilities and gain others that have potential for tissue injury. It is well known that, although immunosuppressive measures are able to control the disease activity of RA, they consistently fail to induce remission. In particular, therapies based on depletion of CD4+ T cells have not yielded any lasting benefit. This is to be expected if the T-cell repertoire is contracted and clonally expanded and the ability of de novo thymic T-cell generation is compromised. Therefore, bone-marrow transplantation, currently advocated for autoimmune diseases, might not be efficacious and could lead to increased morbidity in patients with RA. Our model would predict that the future treatment of RA should shift focus from primary immunosuppression to novel measures of immunoreconstitution.
control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 Goldrath, A.W. et al. (1999) Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183–190 Viret, C. et al. (1999) Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition. Immunity 10, 559–568 Goldrath, A.W. et al. (1999) Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 Jendro, M.C. et al. (1995) Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis. Arthritis Rheum. 38, 1242–1251 Koetz, K. et al. (2000) T cell homeostasis in patients with rheumatoid arthritis. Proc. Natl. Acad. Sci. U. S. A. 97, 9203–9208 Hazenberg, M.D. et al. (2000) Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat. Med. 6, 1036–1042 Weng, N.P. et al. (1995) Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc. Natl. Acad. Sci. U. S. A. 92, 11091–11094 Arstila, T.P. et al. (1999) A direct estimate of the human αβ T cell receptor diversity. Science 286, 958–961 Wagner, U.G. et al. (1998) Perturbation of the T cell repertoire in rheumatoid arthritis. Proc. Natl. Acad. Sci. U. S. A. 95, 14447–14452 DerSimonian, H. et al. (1993) Clonal V alpha 12.1+ T cell expansions in the peripheral blood of rheumatoid arthritis patients. J. Exp. Med. 177, 1623–1631 Schmidt, D. et al. (1996) CD4+ CD7− CD28− T cells are expanded in rheumatoid arthritis and
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are characterized by autoreactivity. J. Clin. Invest. 97, 2027–2037 Behar, S.M. et al. (1998) Clonally expanded V alpha 12+ (AV12S1),CD8+ T cells from a patient with rheumatoid arthritis are autoreactive. Arthritis Rheum. 41, 498–506 Ku, C.C. et al. (1997) CD8+ T-cell clones in old mice. Immunol Rev. 160, 139–144 Posnett, D.N. et al. (1994) Clonal populations of T cells in normal elderly humans: the T cell equivalent to ‘benign monoclonal gammapathy’. J. Exp. Med. 179, 609–618 Vallejo, A.N. et al. (1998) Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity. J. Biol. Chem. 273, 8119–8129 Namekawa, T. et al. (2000) Killer cell activating receptors function as costimulatory molecules on CD4+CD28null T cells clonally expanded in rheumatoid arthritis. J. Immunol. 165, 1138–1145 Warrington, K. et al. CD4+CD28null T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. Arthritis Rheum. (in press) Martens, P.B. et al. (1997) Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum. 40, 1106–1114 Pasceri, V. et al. (1999) A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation 100, 2124–2126 Coakley, G. et al. (2000) CD8+ CD57+ T cells from healthy elderly subjects suppress neutrophil development in vitro: implications for the neutropenia of Felty’s and large granular lymphocyte syndromes. Arthritis Rheum. 43, 834–843 Liuzzo, G. et al. (2000) Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 101, 2883–2888