The most important antibody isotype in the development of immediate type hypersensitivity in humans and mice if IgE. We have found that a peptide derived from the bacteriophage lambdal cI repressor protein, and a variety of its sequence variants, can induce immediate-type (allergic) hypersensitivity responses in mice. 12-26 variants that differ by as little as single amino acid residues deviate greatly in their ability to induce hypersensitivity. Analysis of the T cell and antibody responses to these peptides suggests that only certain peptide-MHC class II antigen combinations stimulate CD4+ T cells to express interleukin-4 (IL-4), resulting in anti-peptide IgE production by the B cell population. The experiments proposed here are designed to elucidate the basis for the differential production of IL-4 (and perhaps other cytokines) by CD4 T cells responding to subtly different forms of 12-26-based synthetic peptides. These experiments will involve: 1) the direct measurement of cytokine production in the responding T cell population using RNA hybridization and single cell ELISA spot assays; 2) the generation of short and long term CD4+ T cell lines and characterization of their in vitro activation requirements and cytokine phenotypes; and 3) the analysis of T cell receptor variable region repertoire and antigenic fine specificity of peptide elicited T cell hybridomas which either do, or do not express IL-4. Our studies promise to provide new insights into the molecular and cellular basis of immediate-type hypersensitivity and the regulation of cytokine production by the murine T cell population. These insights will contribute to the knowledge base needed for rational design of vaccines, as both cell mediated and humoral immune responses appear to be largely regulated via the cytokines produced by the CD4+ T cell compartment.
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