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

Despite tolerance induction of naive MBP-specific CNS T cells, spontaneous EAE still occurs in a percentage of the MBP TCR transgenic mice, primarily within an age window of 5-12 wk (14) . Interestingly, our studies show that at the age when the incidence of spontaneous EAE in MBP TCR1 transgenic mice declines, the number of MBP-specific T cells in the CNS of these mice doubles and their phenotype converts to that of an activated/memory T cell. This increase in activated/memory T cells is due in part to expression of the MBP-specific TCR because the number of memory T cells is greater in the CNS of older TCR transgenic mice than in the CNS of age-matched nontransgenic mice, and much of this increase in MBP TCR transgenic mice can be accounted for by an increase in MBPspecific (V ␣ 2 ϩ ) memory cells. Thus, although T cells in older MBP TCR transgenic mice appear to have encountered antigen more frequently than T cells in older nontransgenic mice, this encounter is not correlated with initiation of disease. Spontaneous EAE may be prevented in older MBP TCR transgenic mice by the development of nontransgenic CD4 ϩ regulatory T cells that have been shown to be critical in prevention of spontaneous EAE (12, 47, 48) . These regulatory T cells must not function by decreasing exposure of MBP-specific T cells to antigen since memory MBP-specific T cells accumulate in older MBP TCR transgenic mice, but rather the regulatory T cells must change the outcome of this interaction.