Thymic presentation of autoantigens and the efficiency of negative selection. (English) Zbl 1042.92008

Summary: Antigen recognition by the adaptive cellular immune system is based on a diverse repertoire of antigen receptors. Since this repertoire is formed by genetic recombination, a number of receptors are autoreactive by chance, giving rise to the threat of autoimmune disease. Potentially autoreactive \(T\) lymphocytes \((T\) cells) are rendered ineffective by various tolerance mechanisms. One of these mechanisms is negative selection, the deletion from the repertoire of immature autoreactive \(T\) cells in the thymus. The present paper shows how to assess the contribution made by negative selection relative to other tolerisation mechanisms by deducing the impact of negative selection on the \(T\) cell repertoire from the statistics of autoantigen presentation in the thymus.


92C37 Cell biology
92C30 Physiology (general)
92C50 Medical applications (general)
Full Text: DOI EuDML


[1] Akkaraju S., Ho W.Y., Leong D., Canaan K., Davis M.M., Goodnow C.C. A range of CD4 T cell tolerance: partial inactivation to organ-specific antigen allows nondestructive thyroiditis or insulitis 1997; 7: 255-271
[2] Anderson A.C., Waldner H., Turchin V., Jabs C., Prabhu Das M., Kuchroo V.K., Nicholson L.B. Autoantigen-responsive T cell clones demonstrate unfocused TCR cross-reactivity toward multiple related ligands: implications for autoimmunity 2000; 202: 88-96
[3] Antonia S.J., Geiger T., Miller J., Flavell R.A. Mechanisms of immune tolerance induction through the thymic expression of a peripheral tissue-specific protein 1995; 7: 715-725
[4] Ardavín C., Wu L., Li C.-L., Shortman K. Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population 1993; 362: 761-763
[5] Arstila T.P., Casrouge A., Baron V., Even J., Kanellopoulos J., Kourilsky P. A direct estimate of the human <emph type=”2”>{\(\alpha\)}</emph>-<emph type=”2”>{\(\beta\)}</emph> 1999; 286: 958-961
[6] van den Berg H.A., Rand D.A. Antigen presentation on MHC molecules as a diversity filter that enhances immune efficacy 2003; 224: 249-267
[7] van den Berg H.A., Rand D.A., Burroughs N.J. A reliable and safe T cell repertoire based on low-affinity T cell receptors 2001; 209: 465-486
[8] van den Berg H.A., Burroughs N.J., Rand D.A. Quantifying the strength of ligand antagonism in TCR triggering 2002; 64: 781-808 · Zbl 1334.92154
[9] Bevan M.J., Hogquist K.A., Jameson S.C. Selecting the T cell repertoire 1994; 264: 796-797
[10] Borghans J.A.M., Noest A., de Boer R.J. How specific should immunological memory be? 1999; 163: 569-575
[11] Bouneaud C., Kourilsky P., Bousso P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion 2000; 13: 829-840
[12] Burnet F.M. 1959; Cambridge University Press
[13] Butz E.A., Bevan M.J. Massive expansion of antigen-specific CD8<emph type=”5”>+</emph> 1998; 8: 167-175
[14] Byers D.E., Lindahl K.F. Peptide affinity and concentration affect the sensitivity of M3-restricted CTLs <emph type=”2”>in vitro</emph> 1999; 163: 3022-3028
[15] Davis M.M., Boniface J.J., Reich Z., Lyons D., Hampl J., Arden B., Chien Y.-h. Ligand recognition by <emph type=”2”>{\(\alpha\)}{\(\beta\)}</emph> 1998; 16: 523-544
[16] Dembo A., Zeitouni O. 1998; Springer Verlag
[17] Egwuagu C.E., Charukamnoetkanok P., Gery I. Thymic expression of autoantigens correlates with resistance to autoimmune disease 1997; 159: 3109-3112
[18] Farr A.G., Rudensky A. Medullary thymic epithelium: a mosaic of epithelial self? 1998; 188: 1-4
[19] Fritz R.B., Zhao M.-L. Thymic expression of myelin basic protein (MBP)–activation of MBP-specific T cells by thymic cells in the absence of exogenous MBP 1996; 157: 5249-5253
[20] Gallucci S., Matzinger P. Danger signals: SOS to the immune system 2001; 13: 114-119
[21] Gavin M.A., Bevan M.J. Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire 1995; 3: 793-800
[22] Grossman Z., Paul W.E. Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses 1992; 89: 10365-10369
[23] Grossman Z., Paul W.E. Autoreactivity, dynamic tuning and selectivity 2001; 13: 687-698
[24] Grossman Z., Singer A. Tuning of activation thresholds explains flexibility in the selection and development of T cells in the thymus 1996; 93: 14747-14752
[25] Hagerty D.T., Allen P.M. Intramolecular mimicry: identification and analysis of two cross-reactive T cell epitopes within a single protein 1995; 155: 2993-3001
[26] Hanahan D. Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity 1998; 10: 214-219
[27] Hawiger D., Inaba K., Dorsett Y., Guo M., Mahnke K., Rivera M., Ravetch J.V., Steinman R.M., Nussenzweig M.C. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions <emph type=”2”>in vivo</emph> 2001; 194: 769-779
[28] Hernández J., Lee P.P., Davis M.M., Sherman L.A. The use of HLA A2.1/p53 peptide tetramers to visualize the impact of self tolerance on the TCR repertoire 2000; 164: 596-602
[29] Hogquist K.A., Tomlinson A.J., Kieper W.C., McGargill M.A., Hart M.C. Identification of a naturally occurring ligand for thymic positive selection 1997; 6: 389-399
[30] Hudrisier D., Kessler B., Valitutti S., Horvath C., Cerottini J.-C., Luescher I.F. The efficiency of antigen recognition by CD8<emph type=”5”>+</emph> 1998; 161: 553-562
[31] Hunt D.F., Henderson R.A., Shabanowitz J., Sakaguchi K., Michel H., Sevilir N., Cox A.L., Appella E., Engelhard V.H. Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry 1992; 255: 1261-1263
[32] Iezzi G., Karjalainen K., Lanzavecchia A. The duration of antigenic stimulation determines the fate of naive and effector T cells 1998; 8: 89-95
[33] Ignatowicz L., Kappler J., Marrack P. The repertoire of T cells shaped by a single MHC/peptide ligand 1996; 84: 521-529
[34] Ignatowicz L., Rees W., Pacholczyk R., Ignatowicz H., Kushnir E., Kappler J., Marrack P. T cells can be activated by peptides that are unrelated in sequence to their selecting peptide 1997; 7: 179-186
[35] Itoh Y., Germain R.N. Single cell analysis reveals regulated hierarchical T cell antigen receptor signaling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4<emph type=”5”>+</emph> 1997; 186: 757-766
[36] Itoh M., Takahashi T., Sakaguchi N., Kuniyasu Y., Shimizu J., Otsuka F., Sakaguchi S. Thymus and autoimmunity: production of CD35<emph type=”5”>+</emph>CD<emph type=”5”>+</emph> 1999; 162: 5317-5326
[37] Janeway C.A., Travers P. 1997; 3rd Ed.
[38] Jardetzky T.S., Lane W.S., Robinson R.A., Wiley D.C. Identification of self peptides bound to purified HLA-B27 1991; 353: 326-329
[39] Jordan M.S., Boesteanu A., Reed A.J., Petrone A.L., Holenbeck A.E., Lerman M.A., Naji A., Caton A.J. Thymic selection of CD4<emph type=”5”>+</emph>CD25<emph type=”5”>+</emph> 2001; 2: 301-306
[40] Kalergis A.M., Boucheron N., Doucey M.-A., Palmieri E., Goyarts E.C., Vegh Z., Luesher I.F., Nathenson S.G. Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex 2001; 2: 229-234
[41] Kappler J.W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus 1987; 49: 273-280
[42] Kisielow P., Blüthmann H., Staerz U.D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4<emph type=”5”>+</emph>8<emph type=”5”>+</emph> 1988; 333: 742-746
[43] Klein L., Klein T., Rüther U., Kyewski B. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium 1998; 188: 5-16
[44] Kurts C., Sutherland R.M., Davey G., Lew A.M., Blanas E., Carbone F.R., Miller J.F.A.P., Heath W.R. CD8 T cell ignorance or tolerance to islet antigens depends on antigen dose 1999; 96: 12703-12707
[45] Kyewski B.A., Fathman C.G., Kaplan H.S. Intrathymic presentation of circulating non-major histocompatibility antigens 1984; 308: 196-199
[46] Lanzavecchia A., Sallusto F. Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells 2000; 290: 92-97
[47] Laufer T.M., Glimcher L.H., Lo D. Using thymus anatomy to dissect T cell repertoire selection 1999; 11: 65-70
[48] Lombardi G., Sidhu S., Batchelor R., Lechler R. Anergic T cells as suppressor cells <emph type=”2”>in vitro</emph> 1994; 264: 1587-1589
[49] Mason D. A very high level of crossreactivity is an essential feature of the T-cell receptor 1998; 19: 395-404
[50] Mason D. Some quantitative aspects of T cell repertoire selection: the requirement for regulatory T cells 2001; 182: 80-88
[51] Mazza G., Housset D., Piras C., Gregoire C., Lin S.-Y., Fontecilla-Camps J.C., Malissen B. Glimpses at the recognition of peptide/MHC complexes by T-cell antigen receptors 1998; 163: 187-196
[52] Meerwijk J.P.M., van Marguerat S., Lees R.K., Germain R.N., Fowlkes B.J., MacDonald H.R. Quantitative impact of thymic clonal deletion on the T cell repertoire 1997; 185: 377-383
[53] Merkenschlager M. Tracing interactions of thymocytes with individual stromal cell partners 1996; 26: 892-896
[54] Merkenschlager M., Benoist C., Mathis D. Evidence for a single-niche model of positive selection 1994; 91: 11694-11698
[55] Merkenschlager M., Graf D., Lovatt M., Bommhardt U., Zamoyska R., Fisher A.G. How many thymocytes audition for selection? 1997; 186: 1149-1158
[56] Morgan D.J., Kreuwel H.T.C., Sherman L.A. Antigen concentration and precursor frequency determine the rate of CD8<emph type=”5”>+</emph> 1999; 163: 723-727
[57] Nicholson L.B., Anderson A.C., Kuchroo V.K. Tuning T cell activation threshold and effector function with cross-reactive peptide ligands 2000; 12: 205-213
[58] Nugent C.T., Morgan D.J., Biggs J.A., Ko A., Pilip I.M., Pamer E.G., Sherman L.A. Characterization of CD8<emph type=”5”>+</emph> 2000; 164: 191-200
[59] Oelke M., Maus M.V., Didiano D., June C.H., Mackensen A., Schneck J.P. <emph type=”2”>Ex vivo</emph> 2003; 9: 619-625
[60] Pittet M.J., Valmori D., Dunbar P.R., Speiser D.E., Liénard D., Lejeune F., Fleischhauer K., Cerundolo V., Cerottini J.-C., Romero P. High frequencies of naive Melan-A/MART-1-specific CD8<emph type=”5”>+</emph> 1999; 190: 705-715
[61] Reay P.A., Matsui K., Haase K., Wülfing C., Chien Y.-H., Davis M. Determination of the relationship between T cell responsiveness and the number of MHC-peptide complexes using specific monoclonal antibodies 2000; 164: 5626-5634
[62] Roncarolo M.-G., Levings M.K. The role of different subsets of T regulatory cells in controlling autoimmunity 2000; 12: 676-683
[63] Savage P.A., Davis M.M. A kinetic window constricts the T cell receptor repertoire in the thymus 2001; 14: 243-252
[64] Scollay R., Godfrey D.I. Thymic emigration: conveyor belts or lucky dips? 1995; 16: 268-273
[65] Sebza E., Mariathasan S., Ohteki T., Jones R., Bachmann M.F., Ohashi P.S. Selection of the T cell repertoire 1999; 17: 829-874
[66] Seddon B., Mason D. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity 1999; 189: 877-881
[67] Seddon B., Mason D. The third function of the thymus 2000; 21: 95-99
[68] Shevach E.M. Regulatory T cells in autoimmunity 2000; 18: 423-449
[69] Smith K.M., Olson D.C., Hirose R., Hanahan D. Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance 1997; 9: 1355-1365
[70] Sospreda M., Ferrer-Francesch X., Domúnguez O., Juan M., Foz-Sala M., Pujol-Borrell R. Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens 1998; 161: 5918-5929
[71] Steinman R.M., Turley S., Mellman I. The induction of tolerance by dendritic cells that have captured apoptotic cells 2000; 191: 411-416
[72] Stevanović S., Schild H. Quantitative aspects of T cell activation–peptide generation and editing by MHC class I molecule 1999; 11: 375-384
[73] Surh C.D., Sprent J. T-cell apoptosis detected <emph type=”2”>in situ</emph> 1994; 372: 100-103
[74] Tanchot C., Lemonnier F.A., Pérarnau B., Freitas A.A., Rocha B. Differential requirements for survival and proliferation of CD8 naı”ve or memory T cells 1997; 276: 2057-2062
[75] Valitutti S., Müller S., Dessing M., Lanzavecchia A. Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy 1996; 183: 1917-1921
[76] Viola A., Lanzavecchia A. T cell activation determined by T cell receptor number and tunable thresholds 1996; 273: 104-106
[77] de Visser K.E., Cordaro T.A., Kioussis D., Haanen J.B.A.G., Schumacher T.N.M., Kruisbeek A.M. Tracing and characterization of the low-avidity self-specific T cell repertoire 2000; 30: 1458-1468
[78] Webb S., Morris C., Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity 1990; 63: 1249-1256
[79] Wong P., Barton G.M., Forbush K.A., Rudensky A.Y. Dynamic tuning of T cell reactivity by self-peptide-major histocompatibility complex ligands 2001; 193: 1179-1187
[80] Zerrahn J., Held W., Raulet D.H. The MHC reactivity of the T cell repertoire prior to positive and negative selection 1997; 88: 627-636
[81] Zippelius A., Pittet M., Batard P., Rufer N., de Smedt M., Guillaume P., Ellefsen K., Valmori D., Liénard D., Plum J., MacDonald H.R., Speiser D.E., Cerrottini J.-C., Romero P. Thymic selection generates a large T cell pool recognizing a self-peptide in humans 2002; 195: 485-494
This reference list is based on information provided by the publisher or from digital mathematics libraries. Its items are heuristically matched to zbMATH identifiers and may contain data conversion errors. It attempts to reflect the references listed in the original paper as accurately as possible without claiming the completeness or perfect precision of the matching.