CD4⁺ and CD8⁺ T cell interactions in IFN-γ and IL-4 responses to viral infections: Requirements for IL-2

Cytokine responses to lymphocytic choriomeningitis virus infections were evaluated, and CD8⁺ T cell, CD4⁺ T cell, and IL-2 contributions delineated. In immunocompetent mice, lymphocytic choriomeningitls virus induced both IFN- γ, and IL-4 as well as IL-2. Experiments in mice either β₂-microglobulin- deficient, lacking MHC class I molecules and CD8⁺ T cells, or Aβ(b)- deficient, lacking MHC class H molecules and CD4⁺ T cells, demonstrated that mixtures of T cell responses were required for optimal ex vivo cytokine productions. Intracellular cytokine expression analyses of cells from immunocompetent and immunodeficient mice showed that CD8⁺ T cells were predominant IFN-γ producers, and that expansion of CD8⁺ T cells primed to make IFN-γ was independent of CD4⁺ T cells in vivo. Studies in IL-2- deficient mice demonstrated that this cytokine promoted IFN-γ and IL-4 responses, and ex vivo experiments showed that exogenous IL-2 was required to maintain high-level IFN-γ production by in vivo-primed CD8⁺ T cells. Conditions associated with cytokine decreases were accompanied by reduced detectable plasma Ab responses. The results indicate that, although IL-2- dependent CD8⁺ T cell proliferation does not require endogenous CD4⁺ T cells, IL-2 production by the CD4⁺ T cells may promote continued cytokine release from activated CD8⁺ T cells. By defining these critical steps in cellular and cytokine interactions for shaping endogenous immune responses, the studies advance understanding of the unique conditions regulating CD8⁺ T cell responses to viral challenges.