DIFFERENTIAL RECOGNITION OF PEPTIDE ANALOGS BY NAIVE VERSES ACTIVATEDPLP 139-151-SPECIFIC CD4(-CELLS() T)

CD4(+) T cells specific for PLP 139-151 induce a relapsing-remitting f orm of EAE which is similar to the human demyelinating disease multipl e sclerosis (MS) in both clinical course and histopathology. Conservat ive and nonconservative amino acid substitutions were introduced at th ree TcR or MHC contact residues within PLP 139-151 to identify fine sp ecificity requirements, at the polyclonal level, for stimulating naive encephalitogenic T cells and for reactivating pre-primed autoreactive T cells as measured by T cell proliferation, cytokine induction, and functional encephalitogenic potential. The results indicate that pepti des with substitutions at position 145 exhibited a significantly dimin ished ability to induce active disease, but these substitutions had li ttle or no effect on the ability to activate PLP 139-151-primed T cell s for proliferation or disease transfer. A conservative or a nonconser vative substitution at position 144 ablated both encephalitogenic pote ntial in active and adoptive EAE models and the ability to induce prol iferative responses in T cells primed to the native peptide. A noncons ervative lysine for glycine, but not a conservative serine substitutio n, at position 146 had similar effects. In contrast to their inability to induce active EAE and stimulate in vitro proliferation of PLP 139- 151-primed T cells, the Y144 and the 146 analog peptides were able to suboptimally reactivate these cells for transfer of adoptive EAE. Furt hermore, the nonencephalitogenic K146 peptide was found to exacerbate in vivo induction of EAE induced by priming with a suboptimal dose of PLP 139-151. These data support the hypothesis that naive neuroantigen -specific CD4(+) T cells have more stringent activation requirements t han do PLP 139-151-specific T cells which have previously encountered antigen. The finding that the analog peptides induced differential pat terns of cytokine production, with LT/TNF-alpha production but not IFN -gamma production correlating with full encephalitogenic potential, su ggests different functional outcomes may result from differential leve ls of signal transduction triggered by the substituted peptides. The s ignificance of these results to the potential development of autoimmun e disease via molecular mimicry and for the development of new strateg ies for preventing and treating T cell-mediated autoimmune diseases is discussed.