A salient feature of the immune system is the remarkable heterogeneity of T lymphocytes and the functional diversity represented by the collection of specialized cellular subsets. T lymphocyte subpopulations can be classified according to the differential expression of T cell receptors, surface markers, adhesion molecules, cytokines and their receptors. A thorough understanding of the phenotype, function and activation requirements of individual T cell subsets is crucial to an understanding of autoimmune disease and the mechanisms of immunity to infection. A newly recognized subdivision of T cells is based on the differential expression of T cell receptors. The T cell receptor (TCR) is a disulfide bond-linked heterodimer composed of an alpha (alpha)- chain paired with a beta (beta)-chain or a gamma (gamma)-chain associated with a delta (delta)-chain. Very early in T cell development, cells become committed to express either alpha and beta chain gene products or gamma and delta proteins. As such, distinct T cell lineages are generated that express either the alpha/beta TCR or the gamma/delta TCR. While T lymphocytes that express the T cell receptor represent a small subset of T cells present in lymphoid organs, gamma/delta T cells appear to predominate in epithelial tissue. This tissue localization may indicate their involvement in """"""""front line"""""""" defense mechanisms by recognition of microbial products or induced self antigens present at these sites. The peritoneal cavity of mice is also a site for preferential expression and induction of gamma/delta T cells. Intraperitoneal injection of pathogenic bacteria or their toxins results in a dramatic increase in frequency and number of peritoneal gamma/delta T cells. Stimulation of peritoneal T cells with bacterial antigens or mitogens results in a preferential expansion of gamma/delta T cells resulting in up to 80% gamma/delta T cells in the blast population. Thus, the highly localized and inducible expression of gamma/delta T cells in the murine peritoneal cavity not only supplies evidence for the role of gamma/delta T cells in microbial immunity but also provides an excellent opportunity for elucidating the function, receptor specificity, and activation requirements of gamma/delta T cells. In this proposal, research will be aimed at understanding the mechanism(s) by which gamma/delta T cells are induced by microbial products. The proposed work will help define the receptor specificity and activation requirements relevant to gamma/delta T cells. Experimental approaches include the identification of surface markers of gamma/delta T cells by flow cytometry, the analysis of gamma/delta T cell function in vitro with special emphasis on cytokines such as IL-7 and IL-1 that promote the proliferation of gamma/delta T cells, and the identification of TCR gene usage by a panel of gamma/delta T cell hybridomas. Several fundamental aspects of gamma/delta T cell biology will be studied with hopes of understanding the role of gamma-delta T cells in immune responses to infectious agents.
