TCR affinity and negative regulation limit autoimmunity

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Abstract

Autoimmune diseases are often mediated by self-reactive T cells, which must be activated to cause immunopathology. One mechanism, known as molecular mimicry, proposes that self-reactive T cells may be activated by pathogens expressing crossreactive ligands1,2,3. Here we have developed a model to investigate how the affinity of the T-cell receptor (TCR) for the activating agent influences autoimmunity. Our model shows that an approximately fivefold difference in the TCR affinity for the activating ligand results in a 50% reduction in the incidence of autoimmunity. A reduction in TCR-ligand affinity to approximately 20 times lower than normal does not induce autoimmunity despite the unexpected induction of cytotoxic T lymphocytes (CTLs) and insulitis. Furthermore, in the absence of a key negative regulatory molecule, Cbl-b4,5, 100% of mice develop autoimmunity upon infection with viruses encoding the lower-affinity ligand. Therefore, autoimmune disease is sensitive both to the affinity of the activating ligand and to normal mechanisms that negatively regulate the immune response.

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Figure 1: Characterizing P14 T-cell responses to variant viruses.
Figure 2: Limited induction of diabetes by the LCMV-L6F variant virus despite effective ex vivo CTL function and islet infiltration.
Figure 3: Effective CTL induction by the LCMV-L6F variant virus with limited diabetes.
Figure 4: Diabetes induction in RIP-gp mice is limited by Cbl-b.

References

  1. 1

    Oldstone, M.B.A. Molecular mimicry and immune-mediated diseases. FASEB J. 12, 1255–1265 (1998).

  2. 2

    Wucherpfennig, K.W. Structural basis of molecular mimicry. J. Autoimmun. 16, 293–302 (2001).

  3. 3

    Benoist, C. & Mathis, D. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nat. Immunol. 2, 797–801 (2001).

  4. 4

    Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211–216 (2000).

  5. 5

    Chiang, Y.J. et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403, 216–220 (2000).

  6. 6

    Wucherpfennig, K.W. & Strominger, J.L. Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).

  7. 7

    Zhao, Z., Granucci, F., Yeh, L., Schaffer, P. & Cantor, H. Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection. Science 279, 1344–1347 (1998).

  8. 8

    Gross, D.M. et al. Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis. Science 281, 703–706 (1998).

  9. 9

    Olson, J.K., Eagar, T.N. & Miller, S.D. Functional activation of myelin-specific T cells by virus-induced molecular mimicry. J. Immunol. 169, 2719–2726 (2002).

  10. 10

    Lang, H.L.E. et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat. Immunol. 3, 940–943 (2002).

  11. 11

    Ohashi, P.S. et al. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305–317 (1991).

  12. 12

    Oldstone, M.B.A., Nerenberg, M., Southern, P., Price, J. & Lewicki, H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65, 319–331 (1991).

  13. 13

    Reiser, J.B. et al. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat. Immunol. 4, 241–247 (2003).

  14. 14

    Kohm, A.P., Fuller, K.G. & Miller, S.D. Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology. Trends Microbiol. 11, 101–105 (2003).

  15. 15

    Sykulev, Y. et al. Kinetics and affinity of reactions between an antigen-specific T cell receptor and peptide-MHC complexes. Immunity 1, 15–22 (1994).

  16. 16

    Matsui, K., Boniface, J.J., Steffner, P., Reay, P.A. & Davis, M.M. Kinetics of T-cell receptor binding to peptide/I-Ek complexes: Correlation of the dissociation rate with T-cell responsiveness. Proc. Natl. Acad. Sci. USA 91, 12862–12866 (1994).

  17. 17

    Lyons, D.S. et al. A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists. Immunity 5, 53–61 (1996).

  18. 18

    Alam, S.M. et al. T-cell-receptor affinity and thymocyte positive selection. Nature 381, 616–620 (1996).

  19. 19

    Tissot, A.C., Ciatto, C., Mittl, P.R.E., Grütter, M.G. & Plückthun, A. Viral escape at the molecular level explained by quantitative T-cell receptor/peptide/MHC interactions and the crystal structure of a peptide/MHC complex. J. Mol. Biol. 302, 873–885 (2000).

  20. 20

    Gascoigne, N.R.J., Zal, T. & Alam, S.M. T-cell receptor binding kinetics in T-cell development and activation. Expert Rev. Mol. Med. 1–17 (2001). Published online 12 February 2001, http://www-ermm.cbcu.cam.ac.uk/01002502h.htm

  21. 21

    Sevilla, N. et al. Virus-induced diabetes in a transgenic model: role of cross-reacting viruses and quantitation of effector T cells needed to cause disease. J. Virol. 74, 3284–3292 (2000).

  22. 22

    Amrani, A. et al. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature 406, 739–742 (2000).

  23. 23

    Pircher, H., Bürki, K., Lang, R., Hengartner, H. & Zinkernagel, R. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342, 559–561 (1989).

  24. 24

    Achour, A. et al. A structural basis for LCMV immune evasion. Subversion of H-2D(b) and H-2K(b) presentation of gp33 revealed by comparative crystal structure analyses. Immunity 17, 757–768 (2002).

  25. 25

    Holmberg, K., Mariathasan, S., Ohteki, T., Ohashi, P.S. & Gascoigne, N.R. TCR binding kinetics measured with MHC class I tetramers reveal a positive selecting peptide with relatively high affinity for TCR. J. Immunol. 171, 2427–2434 (2003).

  26. 26

    Rosette, C. et al. The impact of duration versus extent of TCR occupancy on T cell activation: a revision of the kinetic proofreading model. Immunity 15, 59–70 (2001).

  27. 27

    Weidt, G., Deppert, W., Utermohlen, O., Heukeshoven, J. & Lehmann-Grube, F. Emergence of virus escape mutants after immunization with epitope vaccine. J. Virol. 69, 7147–7151 (1995).

  28. 28

    Ohashi, P.S. et al. Induction of diabetes is influenced by the infectious virus and local expression of MHC class I and TNF-α. J. Immunol. 150, 5185–5194 (1993).

  29. 29

    Yokoi, N. et al. Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat. Genet. 31, 391–394 (2002).

  30. 30

    Pircher, H. et al. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature 346, 629–633 (1990).

  31. 31

    Battegay, M. et al. Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24 or 96 well plates. J. Virol. Methods 33, 191–198 (1991).

  32. 32

    Bachmann, M.F., Speiser, D.E., Zakarian, A. & Ohashi, P.S. Inhibition of TCR-triggering by a spectrum of altered peptide ligands suggests the mechanism for TCR-antagonism. Eur. J. Immunol. 28, 3110–3119 (1998).

  33. 33

    Boulter, J.M. et al. Stable, soluble T-cell receptor molecules for crystallization and therapeutics. Protein Eng. 16, 707–711 (2003).

  34. 34

    Willcox, B.E. et al. TCR binding to peptide-MHC stabilizes a flexible recognition interface. Immunity 10, 357–365 (1999).

  35. 35

    Nguyen, L.T. et al. Tumor growth enhances cross-presentation leading to limited T cell activation without tolerance. J. Exp. Med. 195, 423–435 (2002).

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Acknowledgements

This work was supported by the Canadian Institutes for Health Research grant to P.S.O. and by US National Institutes of Health grants GM39476 and DK61329 to N.R.J.G. K.H. is a fellow of the Cancer Research Institute. P.S.O. holds a Canada Research Chair in infection and immunity. The P14 TCR plasmids used for the surface plasmon resonance experiments were a gift from H. Pircher. The P14 mice were a gift from R. Ahmed. We thank J. Altman (Emory University) for the Db gene with the BirA biotinylation sequence.

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Correspondence to Pamela S Ohashi.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Lower affinity LCMV-L6F and LCMV-C4Y replicate in vivo and induce CTL activity. (PDF 34 kb)

Supplementary Fig. 2

L6F is a weak agonist while C4Y is an antagonist for P14 transgenic T cells. (PDF 55 kb)

Supplementary Fig. 3

Limited induction of diabetes by LCMV-L6F variant in mice with a monoclonal TCR repertoire. (PDF 37 kb)

Supplementary Fig. 4

The absence of Cblb does not affect expression of activation markers on T cells upon LCMV-L6F stimulation. (PDF 121 kb)

Supplementary Table 1

Variant peptide and LCMV characteristics (PDF 23 kb)

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Gronski, M., Boulter, J., Moskophidis, D. et al. TCR affinity and negative regulation limit autoimmunity. Nat Med 10, 1234–1239 (2004) doi:10.1038/nm1114

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