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Transgenic Mice Human gp100 Epitope Using DR4-IE Identification of a MHC Class II-Restricted

CD4 1 T cells play a central role in the induction and persistence of CD8 1 T cells in several models of autoimmune and infectious disease. To improve the efﬁcacy of a synthetic peptide vaccine based on the self-Ag, gp100, we sought to provide Ag-speciﬁc T cell help. To identify a gp100 epitope restricted by the MHC class II allele with the highest prevalence in patients with malignant melanoma (HLA-DRB1*0401), we immunized mice transgenic for a chimeric human-mouse class II molecule (DR4-IE) with recombinant human gp100 protein. We then searched for the induction of CD4 1 T cell reactivity using candidate epitopes predicted to bind to DRB1*0401 by a computer-assisted algorithm. Of the 21 peptides forecasted to bind most avidly, murine CD4 1 T cells recognized the epitope (human gp100 44–59 , WNRQLYPEWTEAQRLD) that was predicted to bind best. Interest-ingly, the mouse helper T cells also recognized human melanoma cells expressing DRB1*0401. To evaluate whether human CD4 1 T cells could be generated from the peripheral blood of patients with melanoma, we used the synthetic peptide h-gp100 to sensitize lymphocytes ex vivo. Resultant human CD4 1 T cells speciﬁcally recognized melanoma, as measured by tumor cytolysis and the speciﬁc release of cytokines and chemokines. HLA class II transgenic mice may be useful in the identiﬁcation of helper epitopes derived from Ags of potentially great clinical utility. The Journal of Immunology, 2000, 164: 3535–3542. restriction element and Ag expression, respectively, were not recognized by either murine CD4 1 T cell line. For all experiments, T cells and targets were cocultured for 24 h and supernatants were measured for IFN- g secretion by ELISA. All experiments were repeated at least three times with similar results using different but comparable targets, thus demonstrating the generalizability of the experimental ﬁndings.