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

• DOI: 10.1073/pnas.0914508107
• Publication Date: 2010-01-21T03:41:01Z
• Authors: Emanual Maverakis; Juscilene S. Menezes; Akio Ametani; Mei Han; David B. Stevens; Yong He; Yan Wang; Yoko Ono; Yoshinori Miyamura; Kit S. Lam; E. Sally Ward; Eli E. Sercarz
• Keywords: 0301 basic medicine; 570; Encephalomyelitis, Autoimmune, Experimental; T-Lymphocytes; Receptors, Antigen, T-Cell; 610; Autoimmunity; Flow Cytometry; 3. Good health; Mice; 03 medical and health sciences; T-Lymphocyte Subsets; Animals; Immunization; Amino Acid Sequence; Lymph Nodes; Oligopeptides; Spleen; Cell Proliferation

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., a microbial 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.