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J. Exp. Med.,
Volume 188, Number 10, November 16, 1998 1875-1882
By
From the Howard Hughes Medical Institute, the Center for Cancer Research, and the Department of
Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Autoimmune diseases result from a failure of tolerance. Although many self-reactive T cells are
present in animals and humans, their activation appears to be prevented normally by regulatory T cells. In this study, we show that regulatory CD4+ T cells do protect mice against the 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 although many self-reactive T cells are present in their thymi and
peripheral 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, 
/
T cells, or 
/
T
cells indicated that / CD4+ T cells were the only cell population capable of controlling the
self-reactive T cells. To confirm the protective role of CD4+ T cells, we performed 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 transferred before the recipient mice manifested any symptoms of the disease. Transfer of CD4+ T cells after the appearance of symptoms of EAE had no protective effect. These
results indicate that at least some CD4+ T cells have a regulatory function that prevent the
activation of self-reactive T cells.
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