Signals involved in T cell activation. I. Phorbol esters enhance responsiveness but cannot replace intact accessory cells in the induction of mitogen-stimulated T cell proliferation.
The role of accessory cells (AC) in the initiation of mitogen-induced T cell proliferation was examined by comparing the effect of intact macrophages (M phi) with that of 4-beta-phorbol 12-myristate 13-acetate (PMA). In high-density cultures, purified guinea pig T cells failed to proliferate in response to stimulation with phytohemagglutinin (PHA), concanavalin A (Con A), or PMA alone. The addition of M phi to PHA or Con A but not PMA-stimulated cultures restored T cell proliferation. The addition of PMA to high-density T cell cultures stimulated with PHA or Con A also permitted [3H]thymidine incorporation, but was less effective than intact M phi in this regard. This action of PMA was dependent on the small number of AC contaminating the T cell cultures as evidenced by the finding that PMA could not support mitogen responsiveness of T cells that had been depleted of Ia-bearing cells by planning, even when these cells were cultured at high density. When PMA was added to T cell cultures supported by optimal numbers of M phi, catalase-reversible suppression of responses was noted. Even in cultures containing catalase, PMA failed to enhance responsiveness above that supported by optimal numbers of M phi. A low-density culture system was used to examine in greater detail the possibility that PMA could completely substitute for M phi in promoting T cells activation. In low-density cultures, mitogen-induced T cell proliferation required intact M phi. PMA could not support responses even in cultures supplemented with interleukin 1-containing M phi supernatants or purified interleukin 2 alone or in combination. Similar results were found in high-density cultures of T cells depleted of Ia-bearing cells. These results support a model of T cell activation in which AC play at least two distinct roles. The initiation of the response requires a signal conveyed by an intact M phi, which cannot be provided by either a M phi supernatant factor or PMA. The response can be amplified by additional M phi or M phi supernatant factors. PMA can substitute for M phi in this regard and can provide the signal necessary for amplification of T cell proliferation supported by small numbers of intact AC.
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D004247:DNA / Q000096:biosynthesis; D006168:Guinea Pigs; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology; D008934:Mitogens / Q000494:pharmacology*; D010704:Phorbols / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000276:immunology / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D007376:Interleukin-2; D008934:Mitogens; D010704:Phorbols; D004247:DNA; D013755:Tetradecanoylphorbol Acetate