This proposal is based upon our observations that both B7 costimulatory molecules and altered forms of the encephalitogenic PLP 139-151 (HSLGKWLGHPDKF) peptide (termed altered peptide ligands, APL) can regulate experimental allergic encephalomyelitis (EAE) by affecting T cell differentiation and cytokine production. The basic theme of this proposal is to identify the mechanisms by which costimulatory B7 molecules and APLs may suppress autoantigen specific pro--inflammatory Th1 cells and enhance functions of antiinflammatory Th2 cells. We have recently generated PLP 139-151 specific Th2 clones which upon adoptive transfer prevent induction of EAE and reverse established disease. However, all the myelin antigen- reactive Th2 cells do not inhibit EAE, raising the critical question as to what are the requirements necessary for generating protective Th2 clones. We propose to i) determine the contribution of the epitopic structure recognized by the Th2 clones towards the protective phenotype. The protective PLP 139-151 specific Th2 clones that we have generated recognize l141/G142 as the primary TcR contract site as opposed to the encephalitogenic Th1 clones that recognize W144 as the primary TcR contract residue. Using our panel of Th2 clones as well as T cell clones generated from B7 deficient and CTLA4-Ig treated mice in project I, we will correlate the epitope specificity (L141/G142 or E1440 witha the protective phenotype. ii) Study the mechanism by which APL inhibit EAE by studying the nature (epitope specificity and cytokine profile) of T cell clones generated by immunization with the SAPL and testing the effects of these clones in regulating EAE upon adoptive transfer and examining the effects of the APL on inhibiting EAE in the B7-1, B7-2, IL-4 and IL-10 deficient mice. iii) study whether strength of signal/stimulus generated by the B7 molecules and APLs may be responsible for altering T cell differentiation and dictate whether a clone will become an encephalitogene Th1 cell or a regulatory Th2/TGFbeta producing cell. This will be accomplished by generating APC by transfection with varying levels of expression of B7-1, B7-2 and class II molecules. These artificial APCs together with different APLs will be utilized to activate T cell clones to correlate strength of signal with the production TH2 vs. Th1 cytokines. These results will provide broad basic information relevant to understanding the immunopathological events in MS and other diseases mediated by autoimmune mechanisms.
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