T-cells are divided into two subsets based on their expression of ab or gd T-cell antigen receptors. Since gd T-cells expand in patients during a number of infections (up to 50% of all T-cells in the peripheral blood), they are likely to be involved in human immunity to infection. Moreover, murine gd T-cells play critical roles in immunity to Mycobacterium tuberculosis since mice lacking gd T-cells succumb to infection. Gd T-cells may also be important in autoimmunity since they expand in the tissues of patients with certain autoimmune diseases. Support for this hypothesis comes from murine models for lupus, autoimmune diabetes, and collagen-induced arthritis, where gd T-cells play regulatory roles limiting autoimmune ab T-cell responses. However, the antigens that activate these regulatory gd T-cells have not been identified and only a few examples of antigens recognized by gd T-cells have been molecularly defined. Recently, the investigator found that the predominant subset of human gd T-cells is stimulated by the staphylococcal superantigen, SEA, and by nonpeptide prenyl pyrophosphate compounds such as isopentenyl pyrophosphate. Prenyl pyrophosphates are essential precursors for isoprenoid compounds that are made in bacteria and man and thus represent both potential foreign as well as self antigens that could activate immune or autoimmune gd T-cells. Gd T-cell recognition of these nonpeptide antigens is mediated by the Vg2Vd2 TCR and utilizes a novel extracellular presentation pathway that does not involve known antigen presenting molecules. The investigators propose to further define recognition by the gd TCR and determine its functional significance.
In Aim 1 Vg2Vd2 TCR binding to the prenyl pyrophosphate antigens and to the SEA superantigen will be measured.
In Aim 2, the antigen presenting molecule for the nonpeptide antigens will be identified by characterizing the antigen presenting cell protein that reacts with a photoaffinity analog of farnesyl pyrophosphate or with mAbs.
In Aim 3, the structural and functional relevance of bacterial 262 and 276 Dalton unconjugated and nucleotide-conjugated prenyl pyrophosphate antigens will be determined.
In Aim 4 the role of Vg2Vd2+ T-cells in the in vivo immune response to Mycobacterium bovis BCG infections in rhesus monkey animal model will be evaluated. These basic studies will provide insights into the mechanisms of antigen recognition by human gd T-cells and should help clarify their role in immunity and autoimmunity.
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