Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity

Maverakis, Emanual, Menezes, Juscilene S., Ametani, Akio, Han, Mei, Stevens, David B., He, Yong, Wang, Yan, Ono, Yoko, Miyamura, Yoshinori, Lam, Kit S., Ward, E. Sally and Sercarz, Eli E. (2010) Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity. Proceedings of the National Academy of Sciences of the United States of America, 107 (6), 2550-2555. (doi:10.1073/pnas.0914508107).

Abstract

To determine the role that competition plays in a molecular mimic's capacity to induce autoimmunity, we studied the ability of naïve encephalitogenic T cells to expand in response to agonist altered peptide ligands (APLs), some capable of stimulating both self-directed and exclusively APL-specific T cells. Our results show that although the APLs capable of stimulating exclusively APL-specific T cells are able to expand encephalitogenic T cells in vitro, the encephalitogenic repertoire is effectively outcompeted in vivo when the APL is used as the priming immunogen. Competition as a mechanism was supported by: (i) the demonstration of a population of exclusively APL-specific T cells, (ii) an experiment in which an encephalitogenic T cell population was successfully outcompeted by adoptively transferred naïve T cells, and (iii) demonstrating that the elimination of competing T cells bestowed an APL with the ability to expand naïve encephalitogenic T cells in vivo. In total, these experiments support the existence of a reasonably broad T cell repertoire responsive to a molecular mimic (e.g., amicrobial agent), of which the exclusively mimic-specific component tends to focus the immune response on the invading pathogen, whereas the rare cross-reactive, potentially autoreactive T cells are often preempted from becoming involved.

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Contributors

Author: E. Sally Ward

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