CD4+ TH1 and TH2 cells differ in several ways. They secrete different cytokines. The express different cell surface molecules and different transcription factors. These different molecules expressed by TH1 and TH2 contribute to their unique functions and to mechanisms that specifically regulate the growth and differentiation of the subsets. We have recently identified a new functional difference between TH1 and TH2 cells. As part of a series of studies to understand better how CD8+ T cells regulate CD4+ T cell responses, we identified a CD8+ T cell response that was Qa-1-restricted and VBeta8-specific and we cloned CD8+ T cell hybridomas with the specificity. These hybridomas respond to TH1 cells and to a lymphoma that express VBeta8 TCR and Qa-1a but not to VBeta8+ Qa-1b+ cells. The hybridomas, however, do not respond to Qa-1a+ VBeta8+ TH2 cells. This is true even for paris of TH1 and TH2 cells that express identical TCRBeta chains. This difference is not due to an affect of cytokines or other products secreted by the CD4+ cells during the time period examined. The data instead suggest that TH1 and TH2 cells differ either in antigen processing or in the expression of cell surface molecules important in T-T interactions. Consistent with this, the difference between TH1 and TH2 cells is preserved after fixation of the CD4+ cells. In this proposal, we will determine the molecular difference(s) between TH1 and TH2 cells that account(s) for their differential ability to be recognized by antigen-specific CD8+ T cells. We will determine when during TH subset differentiation this difference emerges. We will determine if this difference uniquely applies to the recognition of TCR peptide presented by Qa-1 or if CD8+ T cells specific for other peptides presented by MHC class I molecules also distinguish between TH1 and TH2 targets.