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

Several observations support the idea that the increase in memory T cells in Rag ϩ/ϩ MBP TCR transgenic mice results from interactions via the MBP-specific TCR rather than interactions with environmental antigens via endogenously rearranged TCRs. First, the absolute number of CNS T cells per gram of tissue in older MBP TCR transgenic mice is significantly greater than the number found in older nontransgenic mice (1.4 ϫ 10 4 CNS T cells in nontransgenic mice, n ϭ 11; 6.0 ϫ 10 4 CNS T cells in MBP TCR1 mice, n ϭ 10, P ϭ 0.0007; 7.1 ϫ 10 4 CNS T cells in MBP TCR2 mice, n ϭ 3, P ϭ 0.007). This observation suggests that expression of the MBP TCR results in more antigenic stimulation than the diverse repertoire of TCRs expressed in nontransgenic mice. Second, the absolute number of both total MBP-specific (V ␣ 2 ϩ ) T cells and CD45RB low V ␣ 2 ϩ T cells increases with age within the CNS in MBP TCR1 transgenic mice, suggesting that the increase in memory T cells does not simply reflect an in-crease in T cells with endogenously rearranged TCR chains (data not shown, P ϭ 0.00004). These data are in contrast to results from MHC class II-restricted TCR transgenic mice specific for a nonself antigen, pigeon cytochrome C (24) . In this model, there was an increase in peripheral memory T cells as the animals aged; however, this increase was completely in the transgene-negative T cells rather than the transgene-positive T cells. Our data demonstrate that as MBP TCR transgenic mice age, an increasing number of T cells expressing MBP-specific TCRs are activated and converted to a memory phenotype in the absence of spontaneous EAE.