This proposal focus on understanding the development, specificity, and function of gamma-delta T cells, in an effort to elucidate their role in the immune system. The mechanisms which govern their generation, selection, antigen recognition, and function will be investigated. gamma-delta T cell receptor transgenic mice which express the BID and the mycobacteria reactive T cell receptors will be used in many experiments. Molecular biology and cellular immunology techniques will be employed. We will investigate: l) the mechanisms relating the peripheral selection of "BID" gamma- delta T cells by self ligands. - As a continuation of our progress in this model system, we will attempt to: (a) further characterize the genetic element(s) responsible for the selection of BID; (b)identify the structure recognized by BID TCR; (c) define the type of cellular interactions responsible for the selection of BID; and (d) define what governs BID expansion/contraction in vivo following transfer of BID T cells. 2) the factors influencing the extrathymic generation and maturation of pulmonary gamma-delta T cells: - We will continue this aspect of investigation by determining the cause of differential expression of IL-7 in athymic and euthymic pulmonary environment, and the potential contribution of thymic soluble factor(s) in the maturation of RPL which bear fetal TCR rearrangements. 3) the nature of antigen recognition by Vgamma6/Vdelta1 T cells. a) we will attempt to identify the nature of the component in the mycobacterial antigen mixture that stimulates Vgamma6Vdelta1 T cells. b) we will investigate the role of accessory cells in mycobacteria antigen recognition: Specifically, is there a "genuine" mycobacterial antigen presenting molecule for Vgamma6delta1 T cells, or are accessory cells required for other reasons essential for proliferative response? 4) Analyze the function of gamma-delta T cells. - The in vivo development of effector functions of gamma-delta T cells subsequent to infection or immunization with murine plasmodia and mycobacteria antigens will be analyzed, particularly with respect to cytotoxicity and cytokine production. The potential differences in the type of gamma-delta effectors generated at different anatomical sites as a consequence of differences in the microenvironment will be investigated. We will attempt to define the biological properties of gamma-delta T cells in our transgenics which result in their protective effects on malaria infection. Moreover, the induction of IgA switch within the lung intraepithelial will be investigated, particularly regarding the role played by both gamma-delta and alpha-betaCD4+ T cells.