Ia- macrophages and cytokine networks contribute to tumor-induced suppression of CD4+ autoreactive T cells.

Tumor growth changes the functions and phenotypes of macrophages (M phi) and T cells. Suppression of CD4+ T cell autoresponses during tumor growth was contributed primarily by M phi. Tumor-induced alterations in the abilities of these cells to mediate autorecognition were assessed through syngeneic mixed lymphocyte reaction (SMLR) assays. Tumor-bearing host (TBH) M phi were significantly more suppressive (60-90%) than normal host (NH) M phi, and this suppression was caused partly by reduced Ia expression. TBH Ia- M phi were significantly more suppressive (50-80%) than their NH counterparts. The suppression mechanism was controlled partly by prostaglandin E2 (PGE2), because treating cultures with indomethacin and titrated NH and TBH Ia- M phi led to increased T-cell responsiveness, although responsiveness never reached levels of assays containing unseparated M phi. Blocking studies using anti-interferon-gamma (anti-IFN-gamma) monoclonal antibodies (mAb), anti-interleukin 4 (anti-IL-4) mAb, and indomethacin suggested that IFN-gamma, IL-4, and PGE2 contributed to tumor-induced M phi-mediated suppression. Our results suggested that a quantitative shift in M phi phenotype and a qualitative shift in M phi function in addition to differences in cytokine-directed accessory activities are partly responsible for tumor-induced suppression CD4+ T cell autoresponses.