Regulatory T cells in experimental allergic encephalomyelitis. I. Frequency and specificity analysis in normal and immune rats of a T cell subset that inhibits disease

We have shown previously that administration of myelin basic protein (MBP)- reactive T cells to naive Lewis rats induces not only autoimmune encephalom yelitis (EAE) but also a near total resistance to subsequent disease. By is olating the effector cells that are responsible for the resistance, we demo nstrated that disease protection paralleled with increased numbers of a CD8 (+) regulatory T cell (RTC) subset and that co-injection of this RTC subset with encephalitogenic T cells aborted the pathogenic activity of the latte r cells. Here, we show that a radio-sensitive splenic population of RTC als o exists in naive rats that can be recruited and activated to inhibit the o nset of secondary episodes of adoptive EAE, In co-transfer experiments, thi s protective RTC subpopulation can be isolated to neutralize the pathogenic activity of stimulatory MBP-reactive T cells in vivo. We show that the fre quency of RTC with specificity for MBP-reactive T cells in naive rats is tw o orders of magnitude higher than the frequency of MBP-specific precursors, the activity of RTC increases substantially with age and RTC frequencies i ncrease as a consequence of immunization with MBP-reactive cells lines. In specificity studies, we show that RTC isolated from naive rats and RTC from animals primed with one MBP-reactive cell line show cross-reactive respons es to a variety of different MBP-reactive T cell lines. However, following repeated stimulation with a given MBP line, these RTC display a more limite d, clonotypic response to the selecting line and assume a uniform CD8 pheno type, Finally, functional studies with RTC indicate that proliferative and lytic specificities do not necessarily correlate and that activated rat RTC are especially lytic for a Fas-sensitive murine cell line.