The two cytolytic T lymphocyte (CTL) receptors centrally involved in antigen-specific recognition and triggering of responses are the T cell receptor (TCR), which binds antigen, and CD8, which binds conserved determinants on class I proteins. Our previous work has demonstrated that artificial membranes bearing ligands for only these two receptors are ffective in stimulating responses by murine allogeneic CTL and by H-2 restricted, peptidespecific CTL. Using cloned CTL specific for peptides, we have defined some of the parameters which influence formation of the antigenic peptide-class I complex. These studies have demonstrated a critical role for b2-microglobulin in complex formation. Guided by these results from assays of functional recognition, we have obtained preliminary evidence for binding of radiolabeled peptides to purified class I proteins. Proposed studies will define the biochemical parameters for peptide binding to class I and correlate these with functional recognition by CTL. We have also recently obtained evidence that CD8 is 'activated' via the TCR. Only following 'activation' can CD8-class I dependent adhesion of CTL be detected. Furthermore, CD8 binding to class I results in delivery of a transmembrane signal needed to activate at least some CTL responses. Proposed studies will focus on developing a better understanding of the class I structural requirements for effective interaction with 'activated' CD8, and on determining the relative quantitative contributions of TCR and CD8 interactions to antigen binding and activation of CTL responses.
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