Shaping the T cell repertoire to a bona fide autoantigen: lessons from autoimmune gastritis

Shaping the T cell repertoire to a bona fide autoantigen: lessons from autoimmune gastritis Ian R van Driel, Simon Read, Tricia D Zwar and Paul A Gleeson Murine autoimmune gastritis is one of the most well-defined organ-specific autoimmune diseases. CD4+ T cells, which mediate the disease, recognize the highly abundant gastric H+/K+ ATPase heterodimer. The H+/K+ ATPase a subunit is also expressed in the thymus, in an aire-independent manner, whereas the H+/K+ ATPase b subunit is absent from the thymus. Analysis of both H+/K+ ATPase-specific T cell receptor transgenic mice with different affinities for the gastric antigen and mice deficient in the H+/K+ ATPase subunits has provided information on thymic and peripheral selection events. The H+/K+ ATPase antigens play an important role in purging the repertoire of gastritogenic T cells, and recent data have suggested that this tolerance induction occurs primarily in the periphery. The gastritis system provides a powerful approach to determine the impact of peripheral antigen presentation in the target organ draining lymph node on tolerance and autoimmune disease. Addresses The Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia Corresponding author: Gleeson, Paul A ([email protected])

Current Opinion in Immunology 2005, 17:570–576 This review comes from a themed issue on Autoimmunity Edited by Jean-Franc¸ois Bach and Shimon Sakaguchi Available online 7th October 2005 0952-7915/$ – see front matter Crown Copyright # 2005 Published by Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2005.09.016

Murine autoimmune gastritis that occurs after neonatal thymectomy [2] or after CD4+ T cell transfer to lymphopenic recipients [3] is one of the most thoroughly investigated models of organ-specific autoimmunity. These models have been used extensively to investigate disease pathogenesis, the specificity of the immune response and the genetics of gastritis [3]. It is firmly established that a CD4+ T cell response to the gastric H+/K+ ATPase is responsible for the gastritis [4–7], whereas CD8+ T cell responses do not contribute significantly to the pathology. The gastric H+/K+ ATPase consists of two subunits, a (H/ Ka) and b (H/Kb), and is one of the most abundant proteins in gastric parietal cells [8]. T cell responses to both H/Ka and H/Kb are likely to contribute to gastritis [4,9,10]. Four distinct genetic regions that confer susceptibility to autoimmune gastritis have been identified, and three of these four susceptibility loci are non-MHC genes that colocalise with those of type I diabetes [3,11]. The analysis of tolerance to antigens expressed in peripheral organs of transgenic mice has implicated contributions from clonal deletion, anergy, suppression and ignorance, depending on nature of the antigen and the location and level of expression of the antigen [12–18]. The mechanisms that underpin T cell tolerance to bona fide organ-specific autoantigens remain poorly defined, however, particularly to those autoantigens important in the development of autoimmune diseases associated with the gastric/endocrine cluster, such as thyroiditis, diabetes and gastritis. The highly developed mouse models of autoimmune gastritis, together with the abundance of the target antigen in the gastric mucosa and the availability of H+/K+ ATPase-deficient mice [19,20], have resulted in considerable advances in our understanding of the mechanisms of tolerance to these gastric antigens and how self-tolerance can be disrupted, resulting in the development of an autoimmune disease.

Introduction The end stage of autoimmune gastritis, an inflammatory disease affecting the epithelia of the stomach, is pernicious anaemia. Autoimmune gastritis is one of the most common autoimmune diseases and, with a prevalence of 1.9% in Western populations over the age of 60, it is the commonest cause of vitamin B12 deficiency [1,2]. Autoimmune gastritis shares many features with autoimmune diseases of the pancreas, thyroid and gonads. The disease is characterized by a monocytic infiltrate of the gastric mucosa, depletion of differentiated epithelial cells, and T and B cell responses to the gastric H+/K+ ATPase, the proton pump expressed by parietal cells which is responsible for acidification of the gastric lumen [1,2]. Current Opinion in Immunology 2005, 17:570–576

This review will focus on the impact of the individual subunits of the gastric H+/K+ ATPase on shaping the T cell repertoire to these major gastric autoantigens and will discuss the relative contribution of the thymus and periphery in this tolerance induction.

Transgenic H+/K+ ATPase-specific T cell receptor models of autoimmune gastritis Very few mice that express transgenic MHC class IIrestricted T cell receptors (TCRs) specific for self-antigens develop spontaneous autoimmune disease. Hence, the generation of TCR transgenic mice that develop spontaneous autoimmune gastritis has enabled a signifiwww.sciencedirect.com

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cant insight into the initiation, progression and regulation of an organ-specific autoimmune disease. Three MHC class II-restricted TCR transgenic mouse lines have been produced using receptors specific for H+/K+ ATPase subunits. These TCR transgenic mice have differences in the incidence and severity of spontaneous disease. Two of the TCR receptors, derived from the TXA23 and TXA51 T cell clones, are specific for the H/Ka subunit and the third (1E4) is specific for the H/Kb subunit. H/Ka-specific T cells

adult mouse which was immunised with the dominant epitope of H/Kb [24]. Only a small percentage (<10%) of 1E4 TCR transgenic mice spontaneously develop autoimmune gastritis [5,25], even in the absence of CD25+ Treg cells (KL Laurie et al., unpublished). 1E4 T cells have a low affinity for cognate antigen [5,24] and the level of antigen presentation in the gastric environment of normal mice is below the threshold to activate these T cells [26]; however, by using a transgenic approach to elevate presentation of the H/Kb epitope, the incidence of autoimmune gastritis in the 1E4 TCR transgenic mice increased to >80% [25].

TXA23 T cells have a Th1 phenotype and are highly pathogenic, and consistent with this phenotype all A23 TCR transgenic mice spontaneously develop severe autoimmune gastritis [21]. As few as 103 transgenic thymocytes (equivalent to 100 mature CD4+ thymocytes) are required to cause gastritis when transferred to T celldeficient mice [21]. There is evidence that TXA23 T cells are susceptible to suppression by CD25+ Treg cells; firstly, although TXA23 T cells induce severe gastritis after transfer to T cell-deficient mice, TXA23 T cells are unable to induce gastritis in wild-type mice [6]; and secondly, cotransfer of CD25+ Treg cells prevented the induction of disease by TXA23 T cells in T cell-deficient recipients [22]. The spontaneous development of autoimmune gastritis in the A23 transgenic line is probably due to the overwhelming number of transgenic T cells.

The difference in behaviour of A23, A51 and 1E4 transgenic mice is likely to reflect the relative affinity of the TCRs for their target antigen, together with the level of presentation of the individual gastric autoepitopes. The high-affinity TXA23 T cells are activated in the local draining (paragastric) lymph node of the stomach [21], whereas 1E4 cells have a low affinity TCR and require an elevated level of antigen presentation in the paragastric lymph node for activation [25,26]. These findings indicate that T cells with high avidity receptors, such as TXA23, need to be actively tolerized in the normal individual. Our recent data also show that H/Ka-specific T cells are deleted in the periphery of normal mice by a mechanism dependent on the H/Ka antigen (S Read et al., unpublished).

A51 transgenic mice express the TCR of an H/Ka-specific CD4+ Th2 clone. Autoimmune gastritis occurs in A51 mice at a lower frequency (58%) than A23 mice and is characterised by an eosinophilic infiltrate in the gastric mucosa, the presence of IL-4 and the absence of IFN-g [23]. The A51 mouse line demonstrates that a Th2 response to a self antigen can result in pathological organ-specific autoimmunity, contrary to the view that only Th1 responses are pathogenic. As the TXA23 and TXA51 clones were isolated from a gastritic mouse that was thymectomised on day three after birth [6], T cells with A23 and A51 characteristics can be positively selected in a normal neonatal thymus, escape negative selection and emigrate into the periphery. Given their pathogenicity, such T cells can contribute to the immunopathology of autoimmune gastritis induced by day three thymectomy. Non-thymectomised BALB/c mice, however, do not spontaneously develop autoimmune gastritis, and the fate of H+/K+ ATPasespecific T cells with TXA23 and TXA51 characteristics in the periphery of a normal, non-lymphopenic mouse is an important issue that needs exploration. H/Kb-specific T cells

In contrast to TXA23 and TXA51 T cell clones, which were generated from a day three thymectomised mouse, the 1E4 T cell hybridomas were generated from a normal www.sciencedirect.com

T cell tolerance to the gastric H+/K+ ATPase: role of thymus and periphery There is a marked difference in the thymic expression of the two dominant gastric autoantigens. Whereas both H+/ K+ ATPase subunits are highly abundant in the gastric musosa [8], H/Kb appears to be absent from the thymus, or at best marginally expressed [27,28], whereas H/Ka is expressed in thymic epithelial cells and dendritic cells (DCs; [28,29]). Given the different expression patterns of the two gastric autoantigens, autoimmune gastritis is an ideal system to dissect the role of central and peripheral tolerance in purging the repertoire of high avidity tissuespecific T cells.

Contribution of the thymus to the positive and negative selection of H+/K+ ATPase-specific T cells Thymic selection of H/Ka-specific T cells

It is clear that the thymus can have a profound impact on organ-specific tolerance [30] as a wide array of ‘tissuespecific antigens’ are promiscuously expressed in the thymus [28,29], and expression of many of these tissue-specific antigens is under the control of the Aire gene [31]. H/Ka is expressed in medullary thymic epithelial cells and thymic DCs in both mouse [27] and human [28]. The expression levels of H/Ka in aire-deficient mice were similar to expression levels in wild-type mice, however, indicating that thymic expression of H/Ka in Current Opinion in Immunology 2005, 17:570–576

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epithelial cells is aire independent [31]. Interestingly, aire-deficient BALB/c mice, but not aire-deficient C57BL/6 mice develop gastritis with a high frequency [32], indicating that genetic background influences the development of disease caused by aire deficiency. The antigen specificity of the gastritogenic T cells in airedeficient BALB/c mice, however, have not been identified. It is possible that these T cells recognize gastric antigens other than the H+/K+ ATPase that would be efficiently tolerized in a normal thymus.

antigens, mediates negative selection and protection from autoimmunity. Although this does occur in some combinations of TCR and antigen, the novel findings described above [25] challenge this view. Thymic expression might have no affect on thymic selection, as in the case of the A23 TCR and H/Ka, or might enhance positive selection, as with 1E4 TCR and transgenic H/Kb. The outcome of thymic expression of a tissue-specific antigen will depend upon the precise level of the antigen and in which cell types expression occurs.

We have recently investigated the role of the thymic expression of H/Ka in inducing tolerance (S Allen et al., unpublished). Using the A23 TCR transgenic mice on an H/Ka-deficient background we found that thymic H/Ka does not significantly affect thymic selection of the highly pathogenic A23 T cells. Unexpectedly, transgenic expression of the H/Kb in an H/Ka-sufficient thymus resulted in thymic deletion of A23 T cells. This finding can be understood by considering the intracellular trafficking of the H/Ka. Transport of newly synthesized H/Ka from the endoplasmic reticulum (ER) to post-Golgi compartments is known to require H/Kb; in the absence of H/Kb, H/Ka is unable to be exported from the ER and is rapidly degraded [20,33]. The negative selection of A23 T cells upon transgenic expression of H/Kb indicates that H/Kb is required for the stability and presentation of H/Ka epitopes and, furthermore, that the relatively high expression of the H/Ka subunit alone in the thymus probably has minimal influence on negative selection.

Contribution of the periphery in T cell tolerance to H+/K+ ATPase

Thymic selection of low-affinity H/Kb-specific T cells

Although it is generally assumed that thymic expression of tissue-specific antigens mediates tolerance of selfreactive T cells, few studies have assessed the ability of tissue-specific antigens to induce positive selection of self-reactive T cells. This is particularly relevant to lowaffinity self-reactive pathogenic T cells, as these are probably responsible for the development of many organ-specific autoimmune diseases. In 1E4 transgenic mice it was originally noted that a reduced number of thymocytes were positively selected compared to wildtype mice [5]. Inefficient positive selection in 1E4 TCR transgenic mice may result from low abundance of the selecting self-ligand. The selection of low-avidity 1E4 T cells has been examined in mice expressing low levels of the gastric H/Kb epitope as a fusion protein with the invariant chain in MHC class II-positive cells [25]. This resulted in a dramatic increase in positive selection of 1E4 thymocytes. Furthermore, these cells were not negatively selected and were able to seed the periphery. Thus, thymic expression of tissue-specific antigens can, under certain circumstances, enhance positive selection of low avidity, self-reactive T cells. It is often assumed that thymic expression of antigens, such as the promiscuous expression of peripheral autoCurrent Opinion in Immunology 2005, 17:570–576

Even though the thymus appears to make little or no contribution to the tolerance of H+/K+ ATPase-specific T cells, the analysis of H+/K+ ATPase-deficient mice has clearly demonstrated a fundamental role for the gastric antigens in tolerizing the H+/K+ ATPase repertoire. For example, a comparison of T cell responses in H/Kbdeficient and wild-type mice indicated that the H/Kb autoantigen plays a major role in limiting the development of potentially pathogenic H/Kb-specific T cells [34]. Following immunisation, T cell responses to the H/Kb antigen were increased in H/Kb-deficient mice relative to wild-type mice. In addition, unfractionated CD4+ T cells from H/Kb-deficient mice, but not H/Kbexpressing mice, induced autoimmune gastritis after adoptive transfer to athymic BALB/c mice, demonstrating that the H/Kb-specific repertoire from H/Kb-deficient mice is highly pathogenic. This increase in pathogenicity was attributed directly to an increase in the pathogenicity of effector T cells [34]. From these studies it is likely that the H/Kb-specific T cells present in the periphery of normal BALB/c mice [9,35] are the low avidity residue of a T cell repertoire that has been subjected to tolerance induction. We propose that higher affinity T cells are tolerized by clonal deletion or anergy and that the remaining purged population of lower affinity T cells, for example, the 1E4 T cells discussed earlier, are not activated in the normal gastric environment of a healthy individual. CD25+ Treg cells appear to hold the purged repertoire in abeyance but are ineffective at preventing the unpurged repertoire from initiating autoimmunity (Figure 1). Such a model enables the persistence of potentially gastritogenic T cells in the periphery of normal adult mice.

Presentation of gastric antigens in the periphery There is little information concerning the pathways by which tissue-specific antigens are delivered from healthy tissues to antigen-presenting cells (APCs) in the local draining lymph node. A basal level of DC migration from tissues to lymph nodes is observed in the absence of maturation stimuli, providing the opportunity to continuously present tissue-specific antigens. On the basis of in www.sciencedirect.com

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Figure 1

ing these in vitro studies has been the difficulty in tracking self-antigens from their location within tissues to APCs. Given the importance of the peripheral tolerance of H+/K+ ATPase-specific T cells and the abundance of the H+/K+ ATPase in the gastric mucosa, models of autoimmune gastritis provide a unique opportunity to define the presentation pathway(s) of tissue-specific antigens. Indeed, both CD8ahigh and CD8alow DCs from the gastric lymph node acquire parietal cell-derived H/Ka in healthy untreated mice and activate H/Ka-specific T cells in vitro [37]. It is likely that constitutive presentation of the H+/K+ ATPase in the paragastric lymph node is critical for ongoing tolerance induction of high affinity H+/K+ ATPase-specific T cells that continuously seed the periphery from the thymus.

Role of inflammation and Helicobacter pylori infection in induction of autoimmune gastritis

Models for induction of T cell tolerance to the H+/K+ ATPase and activation during inflammation. (a) Normal paragastric node. H+/K+ ATPase-specific T cells of various affinities emigrate from the thymus [5,6]. High affinity T cells are rendered tolerant by contact with the H+/K+ ATPase [34], probably in the periphery. High affinity T cells are stimulated by DCs in the paragastric lymph node presenting epitopes of the H+/K+ ATPase [37]. We suggest that a lack of co-stimulation by immature DCs results in proliferation but the activated T cells fail to differentiate into effector cells and are short lived. Hence, they are lost from the repertoire. Low affinity cells fail to be stimulated in the paragastric lymph node of healthy mice [5,26] and persist in the repertoire. These remaining cells are prevented from causing autoimmune gastritis by CD25+ Treg cells [51]. The stages at which CD25+ Treg cells act to suppress activation of naı¨ve T cells and their differentiation into effector cells capable of causing disease are undefined. (b) Inflamed paragastric node. Events in the lymph node draining the gastric mucosa are depicted. When the gastric mucosa becomes inflamed, for example by infection with H. pylori, DCs mature and migrate into the paragastric lymph node. The DCs can then present epitopes of H/Ka, H/Kb and possibly cross reactive epitopes from H. pylori to residual naı¨ve lower affinity H+/K+ ATPase-specific T cells, stimulating them so that they proliferate and differentiate into effector cells. H+/K+ ATPase-specific effector T cells can emigrate and mediate destruction of the gastric mucosa. Under inflammatory conditions, suppression by CD25+ Treg cells of various stages of the T cell activation pathway is compromised (red crosses) [52].

vitro studies, it has been proposed that T cell recognition of self-peptide–MHC complexes on immature DCs could induce tolerance [36]. As most tissue-specific antigens are low abundance molecules, a severe limitation in extendwww.sciencedirect.com

Inflammation, mediated by pro-inflammatory cytokines or bacterial infection, can result in the induction of autoimmune gastritis. Transgenic expression of GMCSF in the gastric mucosa resulted in spontaneous gastritis, and the development of gastritis in this model is dependent on anti- H+/K+ ATPase T cell responses [38]. Similarly, the frequent detection of Helicobacter pylori infection in individuals with gastric autoimmunity suggests that the ongoing inflammation generated by the Helicobacter specific response can promote stomach-specific autoimmunity [39]. On the basis of antigen specificity of human T cell clones isolated from the gastric mucosa of H. pylori infected humans there is evidence for the cross reactivity of T cells with the H+/K+ ATPase and H. pylori antigens [40]. This has raised the interesting possibility of a role for molecular mimicry in the genesis of human autoimmune gastritis. An alternative interpretation, however, is that the ongoing gastric inflammation induced by H. pylori infection results in an enhanced presentation of gastric antigens and the subsequent activation of either the residual low avidity pathogenic H+/K+ ATPase-specific T cells present in the peripheral pool or the recent thymic H+/K+ ATPase-specific emigrants that would normally be deleted in the periphery. This is particularly relevant, as H. pylori infections are chronic and an extended period of time may be required to enable expansion of gastric-specific T cells with normally a very low precursor frequency. H+/K+ ATPase-specific T cells that also fortuitously cross-react with H. pylori antigens would be expected to expand more vigorously than other H+/K+ ATPase-specific T cells due to a higher level of epitope presentation, leading to an enhanced frequency of such cells.

Role of CD25+ Treg cells in mouse models of autoimmune gastritis A defining feature of CD25+ Treg cells is the high expression of transcription factor Foxp3, which is necesCurrent Opinion in Immunology 2005, 17:570–576

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sary for their development [41–43]. Foxp3-null mice lack CD25+ Treg cells and, as a consequence, develop a lethal autoimmune syndrome [43]. Several mouse models of autoimmune gastritis are associated with a paucity of CD25+ Treg cells, for example thymectomy at day three after birth or transfer of CD25– T cells into a T-cell deficient host. Depletion of CD25+ Treg cells in adult mice does not result in spontaneous development of autoimmune disease whereas depletion of CD25+ Treg cells coupled with a single immunisation with gastric H+/K+ ATPase in complete adjuvant results in chronic gastritis [44,45]. Immunisation-induced autoimmune gastritis in adult mice without depletion of CD25+ Treg cells requires multiple immunisations with mouse gastric H+/K+ ATPase in adjuvant and, furthermore, the resulting gastritis resolves when immunisation ceases [7]. Collectively, these studies suggest that the gastritogenic T cells are activated upon immunisation and migrate to the stomach; however, in the presence of CD25+ Treg cells, gastritogenic T cells are unable to induce a self-sustaining inflammatory response in the gastric mucosa. This is consistent with a model in which CD25+ Treg cells protect against autoimmune pathology in the adult by suppressing self-reactive T cells when an acute inflammatory event has subsided. In contrast to their absence in adult mice, the absence of CD25+ Treg cells has a more profound impact in young animals. Transient depletion of CD25+ Treg cells from 10-day-old mice caused autoimmune gastritis [45]. Similarly, the neutralisation of IL-2 in young BALB/c mice (day 10) for a limited period dramatically reduced the number of CD25+ Treg cells and resulted in autoimmune pathology [46]. Foxp3 mutations result in a variety of severe autoimmune manifestations [43] and the development of disease in Foxp3 mutant mice is also associated with an absence of CD25+ Treg cells from birth. Why CD25+ Treg cells play a more critical role in the neonatal animal compared with the adult is unknown. One possibility is that CD25+Tregs might be important in maintaining homeostasis of naı¨ve T cells [47]. Lymphopeniainduced T cell proliferation occurs naturally in the postnatal period [48], and in the absence of CD25+ Treg cells might exacerbate the expansion of tissue-specific pathogenic T cells. Thus, a lack of CD25+ Treg cells during this period of lymphopenia-induced expansion in the young animal might alter the cytokine milieu and enhance the development of proliferating T cell effector functions [49]. Alternatively, there might be greater potential for autoreactive T cells to respond to tissue-specific selfantigens in the neonatal animal compared to the adult animal. Peripheral naı¨ve T cells migrate into non-lymphoid tissues in neonatal animals but not in adults [50], thus providing an enhanced potential to contact APCs presenting self-antigens. Current Opinion in Immunology 2005, 17:570–576

Concluding remarks Significant progress has been made in understanding T cell tolerance to the gastric antigens. It now appears that the periphery, rather than the thymus, plays a major role in shaping the T cell repertoire to the gastric H+/K+ ATPase. This area of autoimmunity research has revealed the potentially complex issues associated with promiscuous thymic expression on thymocyte selection. Thymic expression of peripheral antigens can result in positive selection, negative selection or have no affect on selection. These findings highlight the need for a more exhaustive analysis of T cell tolerance to a range of different peripheral antigens. Several additional issues now need to be resolved. The mechanism by which high-affinity H+/ K+ ATPase-specific T cells are rendered tolerant in the gastric environment remains to be defined. More information is required concerning CD25+ Treg cell function in vivo and the antigens that these cells recognize. Finally, identification of the gastritis susceptibility genes and the role they play in T cell tolerance and in gastric antigen presentation will be of particular interest. This information will ultimately provide approaches to enhance immunological tolerance to these peripheral autoantigens in susceptible individuals.

Update The work referred to in the text as (S Allen et al., unpublished) is now in press [53].

Acknowledgements Our work is supported by the National Health and Medical Research Council of Australia. TDZ was supported by an Australian Postgraduate Award.

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24. De Silva HD, Alderuccio F, Hock Toh B, van Driel IR, Gleeson PA: Defining T cell receptors which recognise the immunodominant epitope of the gastric autoantigen, the H/K ATPase b-subunit. Autoimmunity 2001, 33:1-4. 25. Laurie KL, La Gruta NL, Koch N, van Driel IR, Gleeson PA: Thymic  expression of a gastritogenic epitope results in positive selection of self-reactive pathogenic T cells. J Immunol 2004, 172:5994-6002. In this study, transgenic expression of an invariant chain– H/Kb253–277 fusion protein was used to increase the presentation of this epitope. Expression of the transgene in the thymus resulted in increased positive selection of the low-affinity 1E4 TCR. Presentation of the H/Kb253–277 epitope by splenocytes was insufficient to activate 1E4 T cells; however, mice carrying transgenes for both the invariant chain fusion protein and the 1E4 TCR had a dramatically higher incidence of gastritis compared with 1E4 TCR single transgenic mice. 26. Laurie KL: Dissection and manipulation of autoreactive T cell responses in autoimmune gastritis [PhD thesis]. Melbourne: University of Melbourne: 2002. 27. Kyewski B, Derbinski J, Gotter J, Klein L: Promiscuous gene expression and central T-cell tolerance: more than meets the eye. Trends Immunol 2002, 23:364-371. 28. Gotter J, Brors B, Hergenhahn M, Kyewski B: Medullary epithelial  cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J Exp Med 2004, 199:155-166. This study is a thorough analysis of the promiscuous expression of tissuespecific genes in the human thymus. Expression of several defined autoantigens, including the gastric H+/K+ ATPase a and b subunits, were examined in both medullary and cortical thymic epithelial cells and thymic DCs. A similar analysis of gene expression by thymic antigen presenting cells in the mouse is provided in [27,29]. 29. Derbinski J, Schulte A, Kyewski B, Klein L: Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2001, 2:1032-1039. 30. Kyewski B, Derbinski J: Self-representation in the thymus: an extended view. Nat Rev Immunol 2004, 4:688-698. 31. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C et al.: Projection of an immunological self shadow within the thymus by the aire protein. Science 2002, 298:1395-1401. 32. Kuroda N, Mitani T, Takeda N, Ishimaru N, Arakaki R, Hayashi Y,  Bando Y, Izumi K, Takahashi T, Nomura T et al.: Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J Immunol 2005, 174:1862-1870. It has been shown that aire-deficient mice have reduced expression of several tissue-specific genes in the thymus. This report describes the development of autoimmune gastritis in aire-deficient mice in a strainrestricted manner, thus BALB/c aire / mice develop autoimmune gastritis, whereas C57BL/6 aire / mice remain disease free. This observation is intriguing given previous reports that expression of the H+/K+ ATPase subunits in the thymus is not affected by loss of aire gene expression [31]. 33. Gottardi CJ, Caplan MJ: Molecular requirements for the cell surface expression of multisubunit ion transporting ATPases: identification of protein domains that participate in Na,K-ATPase and H/K-ATPase subunit assembly. J Biol Chem 1993, 268:14342-14347. 34. Laurie KL, Van Driel IR, Zwar TD, Barrett SP, Gleeson PA: Endogenous H/K ATPase b-subunit promotes T cell tolerance to the immunodominant gastritogenic determinant. J Immunol 2002, 169:2361-2367. 35. De Silva HD, Gleeson PA, Toh BH, van Driel IR, Carbone FR: Identification of a gastritogenic epitope of the H/K ATPase b-subunit. Immunology 1999, 96:145-151. 36. Steinman RM, Turley S, Mellman I, Inaba K: The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000, 191:411-416. 37. Scheinecker C, McHugh R, Shevach EM, Germain RN: Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med 2002, 196:1079-1090. Current Opinion in Immunology 2005, 17:570–576

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38. Biondo M, Nasa Z, Marshall A, Toh BH, Alderuccio F: Local transgenic expression of granulocyte macrophage-colony stimulating factor initiates autoimmunity. J Immunol 2001, 166:2090-2099. 39. Presotto F, Sabini B, Cecchetto A, Plebani M, De Lazzari F, Pedini B, Betterle C: Helicobacter pylori infection and gastric autoimmune diseases: is there a link? Helicobacter 2003, 8:578-584. 40. Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C, van der Zee R, Telford JL, Vandenbroucke-Grauls CM, D’Elios MM et al.: Molecular mimicry between Helicobacter pylori antigens and H+, K+–adenosine triphosphatase in human gastric autoimmunity. J Exp Med 2003, 198:1147-1156. 41. Khattri R, Cox T, Yasayko SA, Ramsdell F: An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003, 4:337-342. 42. Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299:1057-1061. 43. Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003, 4:330-336. 44. McHugh RS, Shevach EM: Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol 2002, 168:5979-5983.

Disruption of CD4+CD25+ Treg cell function in young mice results in the development of autoimmune pathology. In this study, administration of a neutralising anti-IL-2 monoclonal antibody resulted in a loss of CD4+CD25+ Treg cells from both the thymus and the periphery of treated mice. IL-2, produced primarily by CD4+CD25low cells, was shown to be required for the physiological proliferation of peripheral CD4+CD25+ Treg cells. Consistent with this, neutralisation of IL-2 for a limited period in young BALB/c mice resulted in the development of autoimmune gastritis. Similarly treated non-obese diabetic mice developed an array of autoimmune pathology including diabetes, thyroiditis, sialadenitis and neuritis. 47. Stockinger B, Kassiotis G, Bourgeois C: Homeostasis and T cell regulation. Curr Opin Immunol 2004, 16:775-779. 48. Min B, McHugh R, Sempowski GD, Mackall C, Foucras G, Paul WE: Neonates support lymphopenia-induced proliferation. Immunity 2003, 18:131-140. 49. Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, Powrie F: T cells that cannot respond to TGF-b escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 2005, 201:737-746. 50. Alferink J, Tafuri A, Vestweber D, Hallmann R, Hammerling GJ, Arnold B: Control of neonatal tolerance to tissue antigens by peripheral T cell trafficking. Science 1998, 282:1338-1341. 51. Sakaguchi S: Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004, 22:531-562.

45. Laurie KL, Van Driel IR, Gleeson PA: The role of CD4+CD25+ immunoregulatory T cells in the induction of autoimmune gastritis. Immunol Cell Biol 2002, 80:567-573.

52. von Boehmer H: Mechanisms of suppression by suppressor T cells. Nat Immunol 2005, 6:338-344.

46. Setoguchi R, Hori S, Takahashi T, Sakaguchi S: Homeostatic  maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin IL-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005, 201:723-735.

53. Allen S, Read S, DiPaolo R, McHugh RS, Shevach EM, Gleeson PA, van Driel IR: ‘Promiscuous’ thymic expression of an autoantigen gene does not result in negative selection of pathogenic T cells. J Immunol 2005, in press.

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