The long term objective of this application is to understand the role of gamma-delta T cells in the immune system. Experiments proposed here are designed to: 1) investigate the events leading to the selection of the gamma-delta T cell repertoire: a substantial effort will be dedicated to the genetic and structural characterization of the elements responsible for the strain specific selective expansion of a model gamma-delta clonotype, BID. Various experimental approaches will involve formal genetics and molecular biology. BID T cell receptor transgenic mice and hematopoietic chimeric mice will be used to complete these studies and to analyze the cellular interaction leading to the selection of gamma-delta T cells. 2) further dissect the antigen specificities of gamma-delta T cells. The nature of the antigens and antigen presenting molecules for gamma-delta T cells will be investigated. The relationship between mycobacterial products and exogenous or self stress proteins will be assessed with the help of T cell hybrids and monoclonal """"""""genuine"""""""" gamma-delta T cell populations, produced in transgenic mice in which a gamma-delta TcR which recognizes mycobacterial antigens has been introduced. The limits of the self-non self discrimination process will be investigated in the particular case of gamma-delta T cells. 3) analyze the function of gamma-delta T cells. Effector functions such as cytotoxicity and lymphokine production will be studied using polyclonal and monoclonal freshly isolated gamma-delta T cells following TcR stimulation. The possibility of gamma-delta T cells collaborating with pulmonary epithelial cells in inducing IgA production in B cells will be investigated. Selective accumulation of gamma-delta T cells has been reported for human pathological conditions ranging from coeliac disease, sarcoidosis of the lung, to lepromatous granulomas and rheumatoid arthritis. The part played by gamma-delta T cells in these lesions has not yet been determined. To do this, basic knowledge on the biology of gamma-delta T cells has to be expanded. Experiments proposed here are part of this process.l
