The general objective of this project is to define the mechanisms by which human lymphoid cells interact with antigen-presenting cells in order to produce and regulate immune responses. Over the past year, there have been three major efforts underway that are targeted on this objective: 1) dissection of the molecular basis of viral peptide binding and presentation for T-cell recognition by HLA class I molecules; 2) analysis of antigen-presentation pathways for class I- versus class II- restricted antiviral cytotoxic T lymphocyte (CTL) responses; and 3) delineation of the heterogeneity of expressed T-cell receptor (TCR) genes in myelin basic protein (MBP)-reactive T cells obtained from multiple sclerosis (MS) patients. The principle findings are as follow: 1) class I- and class II-restricted T cells can recognize structurally similar, but distinct epitopes of the same viral peptide, and such peptides share a common motif with other peptides that are also recognized by class I- and class II-restricted T cells; 2) common structural features of HLA-A2 molecules can determine the binding and presentation of three diverse viral peptides derived from HTLV-I, human cytomegalovirus (HCMV), and influenza virus; 3) fragments of HLA heavy chains can be successfully expressed in E. coli and utilized together with iodinated beta-2 microglobulin (beta 2m) and peptides to produce a highly specific peptide-binding assay for class I molecules; 4) class II presentation of a cytosolic viral protein can occur in mutant cells that lack HLA-encoded ATP-dependent transporter molecules, whereas class II presentation of a short cytosolic peptide derived from that same viral protein is dependent on such a transporter; and 5) MS patients develop CD4+ CTL responses in vitro to the immunodominant MBP peptide 87-106 that are very heterogeneous at the level of fine specificity, HLA restriction, and TCR V(alpha) and V(beta) usage.
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