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 show that multiple mechanisms are responsible for maintaining the immunologically privileged status of the CNS. Previous work indicated that immunological privilege was the result of the specialized structure of the blood-brain barrier that limited T cell trafficking to activated T cells (7, 9, 10) . Our data support the notion that T cells found in the CNS of wild-type mice are predominantly activated/memory T cells. However, recent experiments in sheep demonstrated that naive lymphocytes infused directly into the blood could circulate through the cerebral spinal fluid (CSF [31] ). Our experiments suggest a basis for reconciling these apparently conflicting findings. We show that the same number of T cells are found in the CNS of nontransgenic, TCR transgenic, and even Rag Ϫ/Ϫ TCR transgenic mice that have very few activated T cells in the periphery. Thus, a similar number of T cells traffic through the CNS of healthy animals regardless of the number of activated T cells present in the periphery. The CNS of nontransgenic mice is enriched in activated/memory T cells, suggesting that activated T cells have a competitive advantage over naive T cells in crossing the blood-brain barrier. However, as the number of activated T cells in the periphery decreases, more naive T cells are able to enter the CNS. This is most clearly illustrated in Rag Ϫ/Ϫ TCR transgenic mice in which there are very few activated T cells in the periphery and the vast majority of T cells in the CNS exhibit a naive phenotype.