TCR affinity and negative regulation limit autoimmunity

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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.


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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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