The proposed studies are aimed at providing a fuller understanding of the regulation and the function of the cytotoxic T lymphocyte (CTL) response. The specific response of murine lymphocytes to allogeneic major (H-2) and minor histocompatibility (H) antigens, and the polyclonal induction of T cells with Con A will be analyzed. The role of soluble factors in the CTL response will be studied. CTL clones specific for H-2 or minor H antigens, which are dependent on both antigen stimulation and IL-2 for continued growth, will be used extensively in this work. The mitogen or antigen induced expression of killing activity by T cell populations which have been depleted of adherent, Ia-positive accessory cells is dependent on a soluble factor other than IL-1 and IL-2 which we refer to as """"""""CTL Differentiation Factor"""""""" (CDF). Experiments are proposed to determine the cellular source of CDF, the stimuli which induce its secretion, at what stage it acts in the CTL response, and to characterize the activity. An effector CTL, capable of lysing target cells, can also secrete immune interferon (IFN) on recognizing antigen. We showed that a number of antigen and IL-2 dependent CTL clones released large amounts of IFN in response to specific antigen or Con A stimulation. The local release of immune IFN may provide another important arm of the CTL effector response. The conditions required to induce IFN release, and whether all CTL, or other T cell types, can secrete IFN will be studied here. Long-term cultures derived from MLC enriched for CTL, as well as cloned, effector CTL may be used for therapeutic functions in the future. We will therefore investigate the ability of cultured CTL to adoptively transfer immunological memory to syngeneic hosts. Conditions which influence the generation of CTL memory cells in vitro and in vivo will be studied. An in vitro assay for lymphocyte homing will be employed to give some indication as to whether cultured CTL will be able to function effectively in vivo.
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