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Fas‐mediated death and sensory adaptation limit the pathogenic potential of autoreactive T cells after strong antigenic stimulation
Author(s) -
Ryan Kelli R.,
McCue David,
Anderton Stephen M.
Publication year - 2005
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0205059
Subject(s) - biology , t cell receptor , t cell , antigen , immunology , microbiology and biotechnology , experimental autoimmune encephalomyelitis , myelin basic protein , myelin , immune system , endocrinology , central nervous system
The ability of autoreactive T cells to induce autoimmune pathology is dependent on their ability to respond to the level of autoantigen presented in the target organ. Emerging evidence suggests that at the population level, T cell sensitivity for self can be reduced by deletion of those cells bearing high‐affinity T cell receptors (TCRs) or by sensory adaptation of individual cells. Here, we have investigated the mechanisms that prevent the induction of experimental autoimmune encephalomyelitis (EAE) when myelin basic protein (MBP)‐reactive T cells are exposed to a strong, antigenic stimulus. Stimulation of MBP‐reactive TCR transgenic T cells with a superagonist peptide led to extensive activation‐induced cell death (AICD) through Fas signaling. Using T cells lacking Fas, we found that disruption of this deletional mechanism only partially increased EAE in response to superagonist, failing to restore susceptibility to the level found in response to the wild‐type MBP peptide. A significant fraction of the MBP‐reactive T cells was able to avoid AICD in response to superagonist, but these cells had a reduced sensitivity for an antigen that correlated with elevated levels of CD5. Therefore, when TCR affinity is fixed, autoreactive T cell sensitivity can be shifted to below a threshold for harm by a combination of AICD and sensory adaptation.