This project will extend previous observations on the effects of histamine on subpopulations of mouse T lymphocytes. Histamine inhibits in vitro T lymphocyte-mediated cytolysis of allogenic target cells and raises intracellular cyclic AMP levels by interaction with a histamine-type 2 receptor. The frequency of histamine receptor-bearing cytoxic T lymphocytes progressively increases during the primary immune response. Histamine receptors are selectively displayed on nonimmune lymphocyte subpopulations, since they are present on splenic T lymphocytes but not splenic B lymphocytes. During "maturation" of T lymphocytes from thymocytes to cortisone-resistant thymocytes to splenic T lymphocytes, there are increases in functional histamine receptors and decreases in functional beta-adrenergic receptors. Specific initial aims of the present project include (1) development of a direct binding assay for histamine receptors, (2) study of the interaction between histamine and other hormones, including beta-adrenergic agents, prostaglandins, cholinergic agents and corticosteroids, (3) isolation, characterization and induction of lymphocyte populations enriched in, and depleted in histamine receptor-bearing cells, (4) assessment of the role of histamine during in vitro induction of cytotoxicity. Further studies will analyze the effects of histamine in vivo, and the relationships between histamine receptors, reaginic antibodies, and release of endogenous histamine during host-versus-graft immunization and graft-versus-host reactions. The effects of histamine will be studied in human leukocytes, to relate its modulation of T lymphocyte proliferation and cytotoxicity to lymphocyte-derived factors that induce chemotaxis of, and histamne release from, basophils. These studies should help define the relationship between histamine and the control of T lymphocyte function.