The mechanism of inhibition of human IL 2 production.

Abstract

The immune response is regulated by the interaction of lymphocytes communicating through the release of soluble mediators, interleukins. Interleukin 2 (IL 2) sustains division of activated lymphocytes with helper and cytolytic functions, and therefore amplifies the effector phase of immunity. The mechanism of IL 2 production by T lymphocytes has been clearly established in mice. It involves a cascade of cellular events, among which the production of lymphocyte-activating factor (LAF, IL 1) by monocytes seems to be an absolute requirement for the differentiation of certain T lymphocytes into IL 2-producing cells. However, in the human a simple depletion of monocytes is known to enhance rather than inhibit IL 2 production by lymphocytes. The experiments here indicate that in the human there is also an absolute need for a minimum number of monocytes (approximatively 1%) in the culture system for IL 2 production by T lymphocytes. Almost complete depletion of adherent monocytes, by adherence to plastic followed by nylon wool filtration and treatment with monoclonal anti HLA-DR antibodies and complement, abrogates IL 2 production by T lymphocytes. The experiments presented here, as well as results from other laboratories, indicate, on the other hand, that in humans inhibition of IL 2 production is also mediated by an excess of monocytes. This inhibition is mediated by soluble products and is blocked by treatment with indomethacin. PGE2 was identified as one of these inhibitory monokines. Lymphoblastoid B cells (Raji, Ramos, and Daudi) were shown to absorb or inactivate PGE2 molecules.A possible mechanism of this inhibition by PGE2 is suggested. Such inhibition was not observed if the T lymphocyte suspension was irradiated (1000 rad) before addition of PGE2 or excess monocytes. These results suggest that activation of a radiosensitive T cell by monokines is required for the inhibition of IL 2 production. A model for the cellular control of human IL 2 production is proposed.