Anti-inflammatory cytokines directly inhibit innate but not adaptive CD8+ T cell functions

Abstract

Virus-specific CD8(+) T cells provide classical adaptive immunity by responding to cognate peptide antigen, but they may also act in an "innate" capacity by responding directly to cytokine stimulation. Here, we examined regulation of these distinct T cell functions by anti-inflammatory cytokines (interleukin-4 [IL-4], IL-10, and transforming growth factor β [TGF-β]). Innate gamma interferon (IFN-γ) production by CD8(+) T cells following exposure to IL-12 plus IL-18, IL-12 plus tumor necrosis factor alpha (TNF-α), or IL-12 plus IL-15 was inhibited by exposure to anti-inflammatory cytokines either before or shortly after stimulation. However, inhibition was not universal, as other activation parameters, including upregulation of CD25 and CD69, remained largely unaltered. In contrast, peptide-specific T cell responses were resistant to inhibition by anti-inflammatory cytokines. This was not due to downregulation of cytokine receptor expression or an inability to signal through cytokine receptors since phosphorylation of STAT proteins remained intact. These results highlight key differences in cytokine-mediated regulation of innate and adaptive T cell functions, which may help balance effective antiviral immune responses while reducing T cell-mediated immunopathology.

Importance: This study demonstrates key differences between the regulation of "innate" and "adaptive" CD8(+) T cell functions following activation by innate cytokines or viral peptide. Innate production of IFN-γ by CD8(+) T cells following exposure to IL-12 plus IL-18, IL-12 plus TNF-α, or IL-12 plus IL-15 was inhibited by exposure to anti-inflammatory cytokines (IL-4, IL-10, and TGF-β). However, inhibition was not universal, as other activation parameters, including upregulation of CD25 and CD69, remained largely unaltered. In contrast, peptide-specific T cell responses were resistant to inhibition by anti-inflammatory cytokines. This distinct regulation of innate and adaptive T cell functions may serve to reduce T cell-mediated immunopathology while still allowing for effective antiviral responses at a site of infection.