CD8+ cytotoxic cells and CD4+ helper cells expressing an antigen receptor composed of the TcR alpha and beta chains constitute the major T cell subsets. Recently, we have used a monoclonal anti-murine CD3 antibody derived in our laboratory to identify a new T cell subset in the fetal and adult thymus of mice. These CD3+, CD8-, CD4- cells appear early in thymic ontogeny, are maintained in the mature thymus throughout adult life, and express a novel TcR composed of a CD3 complex associated with the TcR gamma gene product disulfide-linked to a fourth glycoprotein, termed TcR delta. Although similar TcR gamma delta/CD3-bearing T cells have been identified in humans, the physiological role of the TcR gamma delta/CD3 T cells is at present unknown. The major objective of this study is to determine the physiologic role of this subset of T cells. The repertoire of TcR alpha beta T cells is clearly skewed toward recognition of major histocompatibility complex (MHC) antigens. In contrast, initial studies of TcR gamma delta cells isolated from both mice and humans suggested that these cells functioned in a non-MHC- restricted fashion. In recent studies, we have generated an MHC- specific cytotoxic TcR gamma delta/CD3 cell line from athymic nu/nu mice. This TcR gamma delta-expressing CTL clearly recognizes a beta2-microglobulin-dependent class I molecule. Additional MHC-specific TcR gamma delta T cells from CD3+, CD8-, CD4- peripheral T cells isolated from athymic nu/nu and euthymic mice will be generated and their repertoires compared. Attempts will be made to generate additional antigen-specific TcR gamma delta T cells, identify the ligand for these cells and perform detailed analyses of the TcR gamma delta structure expressed on peripheral CD8-, CD4- T cells. The activation requirements of purified CD3+, CD8-, CD4- peripheral T cells will be studied using anti-TcR- and anti-non-TcR- specific monoclonal antibodies (mAb) to induce proliferation, lymphokine production, and cytolytic activity. The TcR gamma and TcR delta proteins as well as a novel TcR complex expressed on peripheral CD8-, CD4-T cells will be characterized in an attempt to determine the degree of heterogeneity of T cells expressing non-TcR alpha beta proteins. Finally, we will produce mAb against antigen-specific TcR gamma delta-bearing cells as a means of studying the TcR complex and for use as immunomodulating reagents in vivo.
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