MURINE T LYMPHOCYTE SUBSETS AND ALLOGRAFT REJECTION

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T lymphocytes play a central role in cellular and humoral immune responses, and they are responsible for rejection of allografts. Expression of some T cell surface structures correlates with the class of MHC antigen which restricts their responses: generally, CD8 is found on T cells which are restricted by or reactive with class I MHC antigens while CD4 is found on T which are restricted by or reactive with class II MHC antigens. T cells which express CD4 have been subdivided further on the basis of the array of secreted lymphokines: T(H)1 cells secrete IL-2 and IFN-gamma but not IL-4 or IL-5 while T(H)2 cells secrete IL-4 and IL-5 but not IL-2 or IFN-gamma. However, some CD4+ cells do not fit into these categories. While most CD8+ T cells are dependent on growth factors supplied by CD4+ cells, some are helper-independent. Although T cells carry out direct effector functions such as cytolysis and mediate regulatory functions via secreted lymphokines, the mechanisms by which they cause allograft rejection are poorly characterized. Congenic mouse strains which differ in selected regions of the MHC complex provide useful model systems for studying the functions of the different T cell subsets in allograft rejection. Both CD4+ and CD8+ cells appear to be involved in the rejection of murine allografts which differ only in H-2K(b) and I-A(b), while only CD8+ cells appear to be required for rejection of H-2L(d) allografts. The proposed studies will define the kinds of T cells involved in rejection of allografts which differ from the host in specific, defined regions of the MHC complex and with characterizing the mechanisms by which these T cells cause graft rejection. We will: 1) derive cloned T cells reactive with H-2L(d) class I MHC antigen and determine the array of lymphokines produced and the bell surface molecules expressed; 2) characterize the basis for the variable expression of cytolytic activity in some CD8+ CTL which react with H-2L(d) class I MHC antigens; 3) determine whether there are subsets of CD8+ murine T cells corresponding to the T(H)1 and T(h)2 and other subsets of CD4+ murine T cells; and 4) develop strategies for suppressing allograft rejection including use of monoclonal antibodies reactive with lymphokines or cell surface structures on the particular T cells subsets.