The proposed studies focus on the detailed characterization of the 130 kD CD6 membrane glycoprotein found on most immunocompetent T lymphocytes. Little is known about CD6, although anti-CD6 monoclonal antibodies (MAb) used as serotherapeutic anti-T cell reagents cause clinically significant immunosuppression. Studies from the principal investigator's laboratory indicate that anti-CD6 MAb are mitogenic for resting T cells, enhance the autologous mixed lymphocyte reaction (AMLR), diminish the T cell response to antigen after antigenic modulation of CD6 and that the major anti-CD6 responsive cell is the CD4+2H4+ inducer of suppression. This subset of cells may be important in homeostatic autoreactive immune circuits, but is diminished in inflammatory synovial effusions and in the blood of patients with several chronic systemic immune disorders, including SLE.
The aims of the present proposal are: 1) Characterization of the requirements for and mechanisms of T cell activation by anti-CD6 MAb. This includes study of the differing signal requirements for activation of T cells and T cell subpopulations by anti-CD6 MAb and required and synergistic costimulators and the respective consequences of such activation. Phosphorylation states of T cell membrane structures, expression of genes and gene products important in cell growth and effector functions, and cell proliferation will be analyzed. 2) Examination of the effects of anti-CD6 MAb on autoreactivity and regulatory and effector functions. Regulation of Ig production and cytotoxicity by T cell subsets and the phenotypic and functional characteristics of anti-CD6 responsive IL2-dependent T cell clones and tumor cell lines will be examined. 3) Analysis of the consequences of CD6 antigenic modulation form the T cell surface, including the mechanisms of immunosuppression induced by such modulation and the identification and characterization of normal CD3+CD6-T cells. 4) Analysis of CD6 expression and function and the immunomodulatory effects of anti-CD6 MAbs on lymphocytes from patients with chronic immune mediated rheumatic disease. These studies will provide new and fundamental information regarding a molecule likely to be important in normal T cell biology, should yield insights that will contribute to our understanding of activated T cells which participate in autoimmune rheumatic disease and may suggest mechanisms by which the immune response in these and related disorders can be modulated in a beneficial manner.
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