Spontaneous development of encephalitogenic T cells is regulated by age-dependent induction of tolerance (123.11)

Abstract

Abstract Multiple Sclerosis (MS) is an autoimmune disease against CNS and disease onset most often occurs in young adults, suggesting that aging is a critical factor for the development of MS. We examined the effect of aging on the induction of tolerance in the CNS-specific T cells and their differentiation into pathogenic Th1 and Th17 cells in the transgenic (Tg) mice that express HLA-DRB5*0101 and MBP-specific human TCR (3A6) genes isolated from an MS patient. The 3A6-TCR Tg CD4 T cells undergo thymic and peripheral deletion with aging and the surviving CD4 T cells undergo anergy in the periphery. In spite of induction of age-dependent tolerance induction in the MBP-specific CD4 T cells, 3A6 Tg CD4 T cells differentiate into Th1 and Th17 cells in the thymus, migrate into the periphery, and further differentiate into Th1 and Th17 encephalitogenic T cells spontaneously in 5-10-week-old young adult mice. However, increase in age-dependent tolerance reduces the spontaneous development of encephalitogenic T cells. These data suggest that spontaneous development of encephalitogenic T cells is dependent on the balance between age-dependent tolerance induction and spontaneous development of CNS-specific Th1 and Th17 cells.