Reduced Interleukin-4 Receptor α Expression on CD8⁺ T Cells Correlates with Higher Quality Anti-Viral Immunity

With the hope of understanding how interleukin (IL)-4 and IL-13 modulated quality of anti-viral CD8⁺ T cells, we evaluated the expression of receptors for these cytokines following a range of viral infections (e.g. pox viruses and influenza virus). Results clearly indicated that unlike other IL-4/IL-13 receptor subunits, IL-4 receptor α (IL-4Rα) was significantly down-regulated on anti-viral CD8⁺ T cells in a cognate antigen dependent manner. The infection of gene knockout mice and wild-type (WT) mice with vaccinia virus (VV) or VV expressing IL-4 confirmed that IL-4, IL-13 and signal transducer and activator of transcription 6 (STAT6) were required to increase IL-4Rα expression on CD8⁺ T cells, but not interferon (IFN)-γ. STAT6 dependent elevation of IL-4Rα expression on CD8⁺ T cells was a feature of poor quality anti-viral CD8⁺ T cell immunity as measured by the production of IFN-γ and tumor necrosis factor α (TNF-α) in response to VV antigen stimulation in vitro. We propose that down-regulation of IL-4Rα, but not the other IL-4/IL-13 receptor subunits, is a mechanism by which CD8⁺ T cells reduce responsiveness to IL-4 and IL-13. This can improve the quality of anti-viral CD8⁺ T cell immunity. Our findings have important implications in understanding anti-viral CD8⁺ T cell immunity and designing effective vaccines against chronic viral infections.