In Situ Tolerance within the Central Nervous System as a Mechanism for Preventing Autoimmunity

Brabb, Thea; von Dassow, Peter; Ordonez, Nadia; Schnabel, Bryan; Duke, Blythe; Goverman, Joan

Our studies use TCR transgenic mice specific for MBP1-11 (11, 12) , the predominant epitope targeted in EAE in B10.PL mice (13) . MBP1-11-specific T cells in the periphery of TCR transgenic mice are primarily naive and proliferate readily to MBP in vitro (11, 14) . EAE can be induced in these mice by administration of pertussis toxin or 872 In Situ Tolerance within the CNS can occur spontaneously in an environment with increased microbial exposure (14) . In the studies reported here, we analyzed the ability of the MBP1-11-specific T cells to traffic to the CNS in the absence of any exogenous stimulation. Surprisingly, comparable numbers of T cells were isolated from the CNS of both MBP-specific TCR transgenic mice and wild-type mice. In contrast to wild-type mice, however, most of the MBP-specific T cells found in the CNS of young mice exhibited a naive phenotype rather than an activated or memory phenotype. Similar observations were made in TCR transgenic models specific for nonself antigens. TCR transgenic models differ significantly from wild-type mice in that TCR transgenic mice have few activated/memory peripheral T cells. These results indicate that, in the absence of activated T cells in the periphery, naive T cells can traffic to the CNS. Despite the trafficking of naive MBP-specific T cells through the CNS, the majority of MBP TCR transgenic mice do not develop autoimmunity. We show that the lack of spontaneous EAE is due in part to suppression of the responses of naive MBP-specific T cells within the target organ. Furthermore, CNS cells from MBP TCR transgenic mice are able to suppress the response of nontolerant peripheral MBP-specific T cells in vitro. These data demonstrate that CNS autoimmune disease is regulated in part by the induction of tolerance to CNS antigens in situ.