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

MBP-specific T Cells Convert to Memory Cells with Age. The observation that young Rag Ϫ/Ϫ MBP TCR1 transgenic mice have a similar percentage of CD45RB low T cells in the CNS and spleen as nontransgenic mice suggested that interactions with the MBP-specific TCR on these cells promotes the accumulation of T cells with a memory phenotype. Antigenic stimulation could be provided by MBP itself, by a cross-reactive self-antigen, or environmental antigen. In wild-type mice, the percentage of memory T cells increases with age in the peripheral lymphoid compartments, presumably due to an increased number of encounters with environmental antigens (28) . We hypothesized that a similar increase in the number of memory T cells should be observed in MBP TCR1 transgenic mice if T cells in these animals are continuously interacting with antigen. Analyzing T cell populations in the spleen and CNS of MBP TCR1 transgenic mice and nontransgenic mice as a function of age tested this prediction. Rag ϩ/ϩ instead of Rag Ϫ/Ϫ MBP TCR1 transgenic mice were analyzed because older Rag Ϫ/Ϫ MBP TCR transgenic mice exhibit a 100% incidence of spontaneous EAE (12) . In contrast, Rag ϩ/ϩ MBP TCR1 transgenic mice exhibit EAE primarily between 5 to 10 wk of age, but very few cases of EAE are observed in mice Ͼ69 d of age (14) . Older MBP TCR1 transgenic mice (Ͼ69 d) exhibited a significant increase in the percentage of activated/memory cells (CD45RB low , CD44 high ) in both the CNS and the periphery compared with young MBP TCR1 transgenic mice (P ϭ 0.0006; Fig. 3 and Table I ). Furthermore, the age-dependent decrease in naive T cells was significantly greater in MBP TCR1 transgenic mice than in nontransgenic mice (P ϭ 0.0003). A similar age-dependent decrease in naive T cells is seen in MBP TCR2 transgenic mice (data not shown).