MOLECULAR AND GENETIC REQUIREMENTS FOR PREFERENTIAL RECRUITMENT OF TCRBV8S2(-CELLS IN LEWIS RAT EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS()T)

The underlying mechanisms behind the preferential expression of select TCRBV products in certain autoimmune illnesses, such as multiple scle rosis and some models of experimental autoimmune encephalomyelitis (EA E), have principally remained enigmatic. In this study, we examined th e mutual role of nonself-vs self-origin of antigenic myelin basic prot ein (MBP) peptides and given MHC haplotypes in relation to the relativ e frequency of activated TCRBV8S2(+) T lymphocytes in the Lewis (LEW) rat EAE model. Inbred MHC (RT1) congenic LEW rats (LEW (RT1(1)), LEW.1 AV1 (RT1(av1)), and LEW.1W (RT1(u))) were immunized with the 63 to 88 peptide of the guinea pig MBP (MBP(GP)63-88). Additionally, LEW rats w ere immunized with the corresponding autologous rat sequence (MBP(RAT) 63-88). Although EAE ensued in all MBP peptide/LEW rat strain combinat ions, only LEW rats immunized with the heterologous MBP(RAT)63-88 pept ide elicited T cell responses encompassing a bias toward TCRBV8S2(+) e xpression, as determined by flow cytometric analyses. Reduction of TCR BV8S2(+) T cells led to mitigation of disease severity in LEW rats imm unized with MBP(GP)63-88, but not with MBP(RAT)63-88, indicating that critical encephalitogenic characteristics are associated with this T c ell subset. We conclude that the preferential recruitment of TCRBV8S2( +) T cells in the LEW pat EAE model is due to selective, high-avidity recognition of the nonself-MBP(GP)63-88 in the context of the RT1.B-1 molecule. This inference lends support to the notion that the highly r estricted TCR repertoire of the self-MBP-reactive T cells in certain g enetically predisposed multiple sclerosis patients may have its source in a multistep molecular mimicry event.