In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity

Multiple sclerosis (MS) is believed to be an autoimmune disease in which au toreactive T cells infiltrate the central nervous system (CNS). Animal mode ls of MS have shown that CNS-specific T cells are present in the peripheral T cell repertoire of healthy mice and cause autoimmune disease only when t hey are activated by immunization. T cell entry into the CNS is thought to require some form of peripheral activation because the blood-brain barrier prohibits trafficking of this tissue by naive cells. We report here that na ive T cells can traffic to the CNS without prior activation. Comparable num bers of T cells are found in the CNS of both healthy recombinase activating gene (Rag)(-/-) T cell receptor (TCR) transgenic mice and nontransgenic mi ce even when che transgenic TCR is specific for a CNS antigen. Transgenic T cells isolated from the CNS that are specific for non-CNS antigens are phe notypically naive and proliferate robustly to antigenic stimulation in vitr o. Strikingly, transgenic T cells isolated from the CNS that are specific f or myelin basic protein (MBP) are also primarily phenotypically naive but a re unresponsive to antigenic stimulation in vitro. Mononuclear cells from t he CNS of MBP TCR transgenic but nor: nontransgenic mice can suppress the r esponse of peripheral MBP-specific T cells in vitro. These results indicate that naive MBP-specific T cells can traffic to the CNS but do not trigger autoimmunity because they undergo tolerance induction in situ.