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The Influence of T Cell Development on Pathogen Specificity and Autoreactivity

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Abstract

T cells orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T cell receptors on their surface to short peptides derived from foreign proteins bound to protein products of the major histocompatibility (MHC) gene products, which are displayed on the surface of antigen presenting cells. T cells can also interact with peptide-MHC complexes, where the peptide is derived from host (self) proteins. A diverse repertoire of relatively self-tolerant T cell receptors is selected in the thymus. We study a model, computationally and analytically, to describe how thymic selection shapes the repertoire of T cell receptors, such that T cell receptor recognition of pathogenic peptides is both specific and degenerate. We also discuss the escape probability of autoimmune T cells from the thymus.

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References

  1. Bhalerao, J., Bowcock, A.M.: The genetics of psoriasis: a complex disorder of the skin and immune system. Hum. Mol. Genet. 7, 1537–1545 (1998)

    Article  Google Scholar 

  2. Borghans, J.A., Noest, A.J., De Boer, R.J.: Thymic selection does not limit the individual MHC diversity. Eur. J. Immunol. 33, 3353–3358 (2003)

    Article  Google Scholar 

  3. Bousso, P., Bhakta, N.R., Lewis, R.S., Robey, E.: Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296, 1876–1880 (2002)

    Article  ADS  Google Scholar 

  4. Chao, D.L., Davenport, M.P., Forrest, S., Perelson, A.S.: The effects of thymic selection on the range of T cell cross-reactivity. Eur. J. Immunol. 35, 3452–3459 (2005)

    Article  Google Scholar 

  5. Chessman, D., et al.: Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28, 822–832 (2008)

    Article  Google Scholar 

  6. Daniels, M.A., et al.: Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006)

    Article  ADS  Google Scholar 

  7. Deeks, S.G., Walker, B.D.: Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27, 406–416 (2007)

    Article  Google Scholar 

  8. Detours, V., Perelson, A.S.: Explaining high alloreactivity as a quantitative consequence of affinity-driven thymocyte selection. Proc. Natl. Acad. Sci. USA 96, 5153–5158 (1999)

    Article  ADS  MATH  Google Scholar 

  9. Detours, V., Mehr, R., Perelson, A.S.: A quantitative theory of affinity-driven T cell repertoire selection. J. Theor. Biol. 200, 389–403 (1999)

    Article  Google Scholar 

  10. Eisen, H.N., Chakraborty, A.K.: Evolving concepts of specificity in immune reactions. Proc. Natl. Acad. Sci. USA 107, 22373–22380 (2010)

    Article  ADS  Google Scholar 

  11. Flicek, P., et al.: Ensembl 2008. Nucleic Acids Res. 36, D707–D714 (2008)

    Article  Google Scholar 

  12. Hogquist, K.A., Baldwin, T.A., Jameson, S.C.: Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 5, 772–782 (2005)

    Article  Google Scholar 

  13. Huseby, E.S., et al.: How the T cell repertoire becomes peptide and MHC specific. Cell 122, 247–260 (2005)

    Article  Google Scholar 

  14. Huseby, E.S., Crawford, F., White, J., Marrack, P., Kappler, J.W.: Interface-disrupting amino acids establish specificity between T cell receptors and complexes of major histocompatibility complex and peptide. Nat. Immunol. 7, 1191–1199 (2006)

    Article  Google Scholar 

  15. Janeway, C.: Immunobiology: The Immune System in Health and Disease, 6th edn. Garland, New York (2005)

    Google Scholar 

  16. Kardar, M.: Phase transitions in new solvable Hamiltonians by a Hamiltonian minimization. Phys. Rev. Lett. 51, 523–526 (1983)

    Article  MathSciNet  ADS  Google Scholar 

  17. Košmrlj, A., Jha, A.K., Huseby, E.S., Kardar, M., Chakraborty, A.K.: How the thymus designs antigen-specific and self-tolerant T cell receptor sequences. Proc. Natl. Acad. Sci. USA 105, 16671–16676 (2008)

    Article  ADS  Google Scholar 

  18. Košmrlj, A., Chakraborty, A.K., Kardar, M., Shakhnovich, E.I.: Thymic selection of T-cell receptors as an extreme value problem. Phys. Rev. Lett. 103, 068103 (2009)

    Article  ADS  Google Scholar 

  19. Košmrlj, A., et al.: Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection. Nature 465, 350–354 (2010)

    Article  ADS  Google Scholar 

  20. Migueles, S.A., et al.: HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc. Natl. Acad. Sci. USA 97, 2709–2714 (2000)

    Article  ADS  Google Scholar 

  21. Miyazawa, S., Jernigan, R.L.: Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. J. Mol. Biol. 256, 623–644 (1996)

    Article  Google Scholar 

  22. Moszer, I., Glaser, P., Danchin, A.: Subtilist: a relational database for the Bacillus subtilis genome. Microbiology 141(Pt 2), 261–268 (1995)

    Article  Google Scholar 

  23. Naeher, D., et al.: A constant affinity threshold for T cell tolerance. J. Exp. Med. 204, 2553–2559 (2007)

    Article  Google Scholar 

  24. Park, J.M., Deem, M.W.: Correlations in the T-cell response to altered peptide ligands. Phys. A, Stat. Mech. Appl. 341, 455–470 (2004)

    Article  Google Scholar 

  25. Scherer, A., Noest, A., de Boer, R.J.: Activation-threshold tuning in an affinity model for the T-cell repertoire. Proc. Biol. Sci. 271, 609–616 (2004)

    Article  Google Scholar 

  26. Siggs, O.M., Makaroff, L.E., Liston, A.: The why and how of thymocyte negative selection. Curr. Opin. Immunol. 18, 175–183 (2006)

    Article  Google Scholar 

  27. Unanue, E.R.: Antigen-presenting function of the macrophage. Annu. Rev. Immunol. 2, 395–428 (1984)

    Article  Google Scholar 

  28. von Boehmer, H., et al.: Thymic selection revisited: how essential is it? Immunol. Rev. 191, 62–78 (2003)

    Article  Google Scholar 

  29. Werlen, G., Hausmann, B., Naeher, D., Palmer, E.: Signaling life and death in the thymus: timing is everything. Science 299, 1859–1863 (2003)

    Article  ADS  Google Scholar 

  30. Yang, M., Park, J.M., Deem, M.W.: Evolutionary design in biological physics and materials science. Lect. Notes Phys. 704, 541–562 (2006)

    Article  ADS  Google Scholar 

  31. Zhou, H., Deem, M.W.: Sculpting the immunological response to dengue fever by polytopic vaccination. Vaccine 24, 2451–2459 (2006)

    Article  Google Scholar 

Download references

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Correspondence to Mehran Kardar or Arup K. Chakraborty.

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Košmrlj, A., Kardar, M. & Chakraborty, A.K. The Influence of T Cell Development on Pathogen Specificity and Autoreactivity. J Stat Phys 149, 203–219 (2012). https://doi.org/10.1007/s10955-011-0403-8

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  • DOI: https://doi.org/10.1007/s10955-011-0403-8

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