Central tolerance, human autoimmune diseases and tumor immunity

Central tolerance, human autoimmune diseases and tumor immunity


Chloé Michel and Sheena Pinto


Figure 4
© dkfz.de

Tolerance induction by promiscuously expressed TRAs is astoundingly efficient, given that each TRA is only expressed by a minor subset of mTECs amounting to only a few thousand cells per thymus (1-3). Two complementing mechanisms contribute to this efficacy. First, promiscuously expressed antigens are constitutively cross-presented by thymic DC, thus increasing antigen availability within the local vicinity of mTECs (4). Second, thymocytes seem to extensively scan stromal cells within the medulla (reviewed in 5). This latter feature was also implied by the finding that rare mTECs are able to autonomously delete self-reactive T cells (6). Next to deletion, mTECs mediate a second tolerance mode, the generation/selection of self-reactive T regulatory cells. This notion is supported by the efficient generation of T regulatory cells in a transgenic model, expressing a neo-antigen under a neural tissue-specific promoter in a promiscuous fashion (7). The concurrent and constitutive presentation of TRAs by mTECs, the site of their synthesis and cross-presenting thymic DC ensures that both tolerance modes – deletion and selection of T regulatory cells – operate in both cell types for this important set of self-antigens (reviewed in 8) (Fig. 4).

It is increasingly appreciated that defects in central tolerance towards single or groups of TRAs have to be considered as potential risk factors for organ-specific human autoimmune disease, such as Multiple Sclerosis, Myasthenia gravis, Type 1 Diabetes mellitus (T1 DM), Autoimmune Myocarditis, or the Autoimmune Polyglandular Syndrome (APS-1). Several distinct mechanisms can cause subtle or more profound impairments of central tolerance towards TRAs due to qualitative or quantitative alterations in pGE. Thus, differences in splicing (9) and posttranslational glycosylation (3) between thymic and tissue-specific antigen expression might result in escape of high-avidity auto-reactive T cells. In the same vein, the level of intra-thymic self-antigen expression can influence the threshold of self-tolerance. In animal models the threshold of central tolerance towards such TRAs is surprisingly sensitive towards minor shifts in antigen expression levels and this is apparently also the case in humans (2,10). Thus, a single nucleotide polymorphism (SNP) in the promoter region of the alpha-chain of the Acetylcholine Receptor (AChR-a) gene also influenced transcription levels of this auto-antigen in the thymus and correlated with the onset of the associated autoimmune disease Myasthenia gravis (10, Fig. 5). This SNP in the AChR gene represents the first case to show that a SNP in the promoter region of an auto-antigen influences its intra-thymic transcription levels and correlates with susceptibility to an associated organ-specific autoimmune disease. Apart from subtle SNP-correlated differences in TRA expression levels (11), some self-antigens are essentially missing in mTECs, such as GAD65 (12) and the myosin heavy chain alpha (13). Intriguingly, these self-antigens are major target antigens in the early disease course of Type 1 diabetes mellitus and Autoimmune Myocarditis, respectively as reflected by elevated frequencies of specific auto-reactive T cells and levels of auto-antibodies. Yet another mechanism to evade central tolerance is mis-iniated transcription of TRAs in mTECs, as is the case for the melanoma tumour antigen MART-1 gene. Mis-initiation results in transcription of truncated mRNA isoforms excluding a 5 prime T cell epitope. Lack of central tolerance towards this epitope is associated with an unusually high frequency of epitope-specific CD8 T cells in the periphery (14).

Figure 5
© dkfz.de

It is important to note that contrary to commonly held views, tumor-associated antigens, including cancer germ cell antigens (i.e. MAGE antigens), so-called onco-fetal antigens (i.e. carcinoma-embryonic antigens, CEA) and differentiation antigens (i.e. MUC1) are promiscuously expressed in human mTECs. This questioned the notion that these antigens, due to their restricted spatio-temporal expression pattern in normal tissues, are largely exempt from self-tolerance and thus preferable candidates for tumor vaccination (3,12). Instead we surmise that promiscuous expression of these tumor-associated antigens results in immunological tolerance in humans, as is the case for other TRAs. Indeed, we could show that transgenic expression of human CEA in mouse mTECs resulted in tolerisation of a major fraction of the specific-CD4 T cell repertoire, thereby markedly limiting the efficacy of CEA-specific immunization against CEA-expressing tumors (15). Whether central tolerance contributes to the modest success of current clinical vaccination trials with peptides derived from these self-antigens remains conjectural.

Selected Publications

1. Derbinski, J., A. Schulte, B. Kyewski and L. Klein. 2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032-1039.

2. Taubert, R., J. Schwendemann and B. Kyewski. 2007. Highly variable expression of tissue-restricted self-antigens in human thymus: implications for self-tolerance and autoimmunity. Eur J Immunol. 37, 838-848.

3. Cloosen, S., A. Arnold, M. Thio, G.M.J. Bos, B. Kyewski and W.T.V. Germeraad. 2007. Tumor-associated antigens are co-expressed in rare medullary thymic epithelial cells. Cancer Res. 67, 3919-3926.

4. Koble, C. and B. Kyewski. 2009. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206, 1505-1513.

5. Kyewski, B. and L. Klein. 2006. A central role for central tolerance. Annu. Rev. Immunol. 24: 571-606.

6. Klein L., B. Röttinger and B. Kyewski. 2001. Sampling of complementing self-antigen pools by thymic stromal cells maximizes the scope of central T-cell tolerance. Eur. J. Immunol. 31, 2476-2486.

7. Cabarrocas, J., C. Cassan,, F. Magnusson,., F. Piaggio, L. Mars, J. Derbinski, B. Kyewski, D. Gross, B. Salomon, K. Khazaie, A. Saoudi and R. S. Liblau. 2006. Foxp3+ CD25+ regulatory T cells specific for a neo-self-antigen develop at the double-positive thymic stage. Proc. Natl. Acad. Sci. USA 103, 8453-8458.

8. Klein, L., B. Kyewski, P.M. Allen, K.A. Hogquist. 2014. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14:377-91.

9. Klein, L., M. Klugmann, K. Nave, V.K. Tuohy and B. Kyewski. 2000. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6, 56-61.

10. Giraud, M., R. Taubert, C. Vandiedonck, X. Ke, M. Levi-Strauss, F. Pagani, F. Baralle, B. Eymard, C. Tranchant, P. Gajdos, A. Vincent, N. Willcox, D. Beeson, B. Kyewski and H. Garchon. 2007. An IRF8-binding promotor variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934-937.

11. Colobran, R., M. del Pilar Armengol, R. Faner, M. Gärtner, L.-O. Tykocinski, A. Lucas, M. Ruiz, M. Juan, B. Kyewski, R. Pujol-Borrell. 2011. Association of a SNP with intrathymic transcription of TSHR and Graves’ disease: a role for defective thymic tolerance. Human Mol. Genet. 20:3415-3423.

12. Gotter, J., B. Brors, M. Hergenhahn, and B. Kyewski. 2004. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes co-localized in chromosomal clusters. J. Exp. Med. 199, 155-166.

13. Lv, H, E. Havari, S. Pinto, R.V. Gottumukkala, L. Cornivelli, K. Raddassi, T. Matsui, A. Rosenzweig, R.T. Bronson, R. Smith, A.L. Fletcher, S.J. Turley, K. Wucherpfennig, B. Kyewski, and M.A. Lipes. 2011. Impaired thymic tolerance to a-myosin directs Autoimmunity to the heart in mice and humans. J. Clin. Invest. 121:1561-73.

14. Pinto, S., D. Sommermeyer, C. Michel, S. Wilde, D. Schendel, W. Uckert, T. Blankenstein, B. Kyewski. 2014. Mis-initiation of intrathymic MART-1 transcription and biased TCR usage explain the high frequency of MART-1 specific T cells. Eur. J. Immunol. 44:2811-2821.

15. Bos, R., S. van Duikeren, T. van Hall, P. Kaaijk, R. Taubert, B. Kyewski, L. Klein, C.J.M. Melief and R. Offringa. 2005. Expression of a natural tumor antigen by thymic epithelial cells inpairs the tumor-protective CD4+ T-cell repertoire. Cancer Res. 65, 6443-6449.

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