CD4(-CELLS PREVENT SPONTANEOUS EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN ANTIMYELIN BASIC-PROTEIN T-CELL RECEPTOR TRANSGENIC MICE() T)

Autoimmune diseases result from a failure of tolerance. Although many self-reactive T cells are present in animals and humans, their activat ion appears to be prevented normally by regulatory T cells. In this st udy, we show that regulatory CD4(+) T cells do protect mice against th e spontaneous occurrence of experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. Anti-myelin basic protein (MBP) TCR transgenic mice (T/R+) do not spontaneously develop EAE alt hough many self-reactive T cells are present in their thymi and periph eral lymphoid organs. However, the disease develops in all crosses of T/R+ mice with recombination-activating gene (RAG)-1 knockout mice in which transgenic TCR-expressing cells are the only lymphocytes present (T/R- mice). In this study, crosses of T/R+ mice with mice deficient for B cells, CD8(+) T cells, NK1.1 CD4(+) T (NKT) cells, gamma/delta T cells, or alpha/beta T cells indicated that alpha/beta CD4(+) T cells were the only cell population capable of controlling the self-reactiv e T cells. To confirm the protective role of CD4(+) T cells, we perfor med adoptive transfer experiments. CD4(+) T cells purified from thymi or lymph nodes of normal mice prevented the occurrence of spontaneous EAE in T/R- mice. To achieve full protection, the cells had to be tran sferred before the recipient mice manifested any symptoms of the disea se. Transfer of CD4(+) T cells after the appearance of symptoms of EAE had no protective effect. These results indicate that at least some C D4(+) T cells have a regulatory function that prevent the activation o f self-reactive T cells.