Endogenous CD4+BV8S2− T cells from TG BV8S2+ donors confer complete protection against spontaneous experimental encephalomyelitis (Sp‐EAE) in TCR transgenic, RAG −/− mice

To investigate regulatory mechanisms which naturally prevent autoimmune diseases, we adopted the genetically restricted immunodeficient (RAG‐1 −/− ) myelin basic protein (MBP)‐specific T cell receptor (TCR) double transgenic (T/R−) mouse model of spontaneous experimental autoimmune encephalomyelitis (Sp‐EAE). Sp‐EAE can be prevented after transfer of CD4+splenocytes from naïve immunocompetent mice. RAG‐1+ double transgenic (T/R+) mice do not develop Sp‐EAE due to the presence of a very small population (about 2%) of non‐Tg TCR specificities. In this study, CD4+BV8S2+ T cells that predominate in T/R+ mice, and three additional populations, CD4+BV8S2−, CD4−CD8−BV8S2+, and CD4−CD8+BV8S2+ T cells that expanded in T/R+ mice after immunization with MBP‐Ac1‐11 peptide, were studied for their ability to prevent Sp‐EAE in T/R− mice. Only the CD4+BV8S2− T cell population conferred complete protection against Sp‐EAE, similar to unfractionated splenocytes from non‐Tg donors, whereas CD4−CD8−BV8S2+ and CD4+BV8S2+ T cells conferred partial protection. In contrast, CD4−CD8+BV8S2+ T cells had no significant protective effects. The highly protective CD4+BV8S2− subpopulation was CD25+, contained non‐clonotypic T cells, and uniquely expressed the CCR4 chemokine receptor. Protected recipient T/R− mice had marked increases in CD4+CD25+ Treg‐like cells, retention of the pathogenic T cell phenotype in the spleen, and markedly reduced inflammation in CNS tissue. Partially protective CD4+BV8S2+ and CD4− CD8−BV8S2+ subpopulations appeared to be mainly clonotypic T cells with altered functional properties. These three Sp‐EAE protective T cell subpopulations possessed distinctive properties and induced a variety of effects in T/R− recipients, thus implicating differing mechanisms of protection. © 2002 Wiley‐Liss, Inc.