IA⁻ Macrophages and Cytokine Networks Contribute to Tumor-Induced Suppression of CD4⁺ Autoreactive T Cells

Abstract

Tumor growth changes the functions and phenotypes of macrophages (Mϕ) and T cells. Suppression of CD4⁺ T cell autoresponses during tumor growth was contributed primarily by Mϕ. 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) Mϕ were significantly more suppressive (60–90%) than normal host (NH) Mϕ, and this suppression was caused partly by reduced la expression. TBH la⁻ Mϕ 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 la⁻ Mϕ led to increased T-cell responsiveness, although responsiveness never reached levels of assays containing unseparated Mϕ. Blocking studies using anti-interferon-gamma (anti-IFN-γ) monoclonal antibodies (mAb), anti-interleukin 4 (anti-IL-4) mAb, and indomethacin suggested that IFN-γ, IL-4, and PGE₂ contributed to tumor-induced Mϕ-mediated suppression. Our results suggested that a quantitative shift in Mϕ phenotype and a qualitative shift in Mϕ function in addition to differences in cytokine-directed accessory activities are partly responsible for tumor-induced suppression CD4⁺ T cell autoresponses.