Peptide antagonists inhibit proliferation and the production of IL-4 and/or IFN-gamma in T helper 1, T helper 2, and T helper 0 clones bearing the same TCR.

Engagement of a TCR by its peptide Ag bound by MHC class II molecules leads to T cell activation, resulting in proliferation and cytokine production. This agonist response can be antagonized by analogue peptides containing single amino acid substitutions. We used T cell clones isolated from a mouse transgenic for the rearranged TCR alpha- and beta-chains of the D10.G4.1 (D10) Th2 clone specific for hen egg conalbumin peptide 134-146 (CA 134-146) to characterize antagonist peptides for the D10.TCR. The D10.TCR CD4 T cell clones proliferated in a dose-dependent manner to CA 134-146, and this proliferation was accompanied by secretion of IL-4 and/or IFN-gamma with Th1, Th2, and Th0 patterns. Proliferation of the clones was inhibited completely by CA 134-146 analogue peptides containing a substitution of the glutamic acid at position 8 with alanine (E8A) or threonine (E8T). The E8A and E8T peptides also antagonized the production of mRNA and subsequent cytokine secretion of IFN-gamma and/or IL-4. Our results, showing that antagonist peptides can inhibit both T cell proliferation and cytokine production in Th1, Th2, and Th0 clones all bearing the same TCR, demonstrate that the TCR:peptide interaction determines the outcome regardless of the phenotype of the clone. Thus, antagonism by peptides acts through the TCR.