THE LY-49 FAMILY - REGULATION OF CYTOKINE PRODUCTION IN MURINE NK CELLS

Most proteins encoded by members of the Ly-49 gene family are class I- recognizing receptors on murine natural killer (NK) cells. Class I rec ognition by Ly-49 receptors usually results in inhibition of Nh cell I ysis of target cells. However, Nh cells function not only in a lytic c apacity, but also can mediate cytokine production. In this report we h ave demonstrated the ability of Ly-49A and Ly-49G2 to inhibit producti on of cytokines by NK cells by showing that specific antibodies agains t these gene products stimulate cytokine production. Murine NK cells w ere cultured in the presence of P815 (H2-D-d), and supernatants were a nalyzed for the production of interferon-gamma (IFN-gamma), tumor necr osis factor alpha (TNF-alpha), and granulocyte-macrophage colony-stimu lating factor (GM-CSF). Nh cell populations were sorted for Ly-49A(+) or Ly-49G(+) subsets, and these subsets were analyzed for their abilit y to alter cytokine induction by target cell interaction. In the prese nce of target cells expressing the appropriate class I molecules, Ly-4 9A and 62 were found to inhibit cytokine induction by Nh cells. Examin ation of mRNA for IFN-gamma and GM-CSF indicated that Ly-49 receptors increased mRNA levels of Nh cells. These results demonstrate that clas s I binding of these Nh receptors can inhibit production of important physiological cytokines, in addition to the regulation of cytotoxic ac tivity.