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 investigation of the mechanism of tolerance induction in naive MBP-specific T cells entering the CNS showed that tolerance does not occur through downregulation of TCR or CD4 because the expression of these receptors on CNS T cells is comparable to that observed on peripheral T cells (data not shown). Inhibition of proliferation of CNS MBP-specific T cells is not mediated by inhibitory factors found in the CSF or brain during inflammation that appear to modulate T cell activity (40, 41) . These factors operate within the microenvironment of the inflamed CNS and would not be present in our in vitro cultures. In addition, naive CD4 Ï© T cells specific for non-CNS antigens proliferate equally well when they are isolated from either the CNS or LNs, and it is only T cells from MBP TCR transgenic mice that are nonresponsive. Our data suggest instead that the interaction of naive MBPspecific T cells with antigen in the CNS results in an irreversible state of nonresponsiveness that is maintained even in the absence of soluble factors found in CNS microenvironments during inflammation. The nonresponsiveness induced in MBP-specific T cells in situ was not reversed by addition of exogenous IL-2 in vitro; however, in vivo induction of T cell anergy is not necessarily overcome by addition of exogenous IL-2 (42) (43) (44) (45) (46) . Influenza hemagglutinin-specific TCR transgenic T cells that have been anergized in vivo have been shown to contain high levels of IL-4 and IL-10 mRNA, suggesting that the anergic T cells may function as regulatory T cells (46) . This phenomenon could explain our finding that mononuclear cells isolated from the CNS of MBP TCR transgenic mice are capable of suppressing the proliferation of nontolerant peripheral MBP-specific T cells in vitro. Investigation is underway to determine which cell types mediate the suppression and whether this bystander suppression is mediated by soluble factors and/or is cell contact dependent.