The general objective of this project is to define the mechanisms by which human lymphoid cells interact with each other and with foreign antigen-bearing cells in order to produce and regulate immune responses. Over the past year, there have been two major efforts underway that are targeted on this objective: 1) dissection of the molecular basis for T cell recognition of class I HLA gene products; and 2) analysis of human T cell receptor gene usage in alloreactive T cell populations. The definition of the structural features of class I HLA molecules that are important for T cell recognition has been pursued using site-directed mutagenesis of a previously defined HLA-A3 variant and by isolating, sequencing, and manipulating additional T cell-defined variants of HLA-A2. The results of these studies demonstrate that a single amino acid change (substitution of valine for glutamic acid) at position 152 in the alpha 2 domain of the A3 heavy chain produces major structural changes in the epitopes that are recognized by both HLA-restricted and alloreactive cytotoxic T lymphocytes (CTL). The importance of residues in the region 147-160 for HLA-restricted CTL recognition was confirmed by the findings of amino acid changes in this region in two different HLA-A2 variant genes (M7A2.2 and DK1A2.3) that we have isolated and sequenced. Analysis of the diversity of T cell receptor beta chain gene usage indicates that although a larger number of V-beta genes can be used to recognize a particular allospecificity, a limited number of V-beta genes will ultimately predominate in the response.
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