Reduced interleukin-4 receptor α expression on CD8+ T cells correlates with higher quality anti-viral immunity

• Published in: PloS one 2013, Vol.8 (1), p.e55788-e55788
• Main Authors: Wijesundara, Danushka K, Tscharke, David C, Jackson, Ronald J, Ranasinghe, Charani
• Format: Article
• Language: English
• Subjects: Animals; Antiviral agents; Biology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cytokines; Down-regulation; Female; Gene Expression Regulation; Immunity; Infections; Influenza; Interferon; Interferon-gamma - genetics; Interferon-gamma - metabolism; Interleukin 13; Interleukin 4; Interleukin-13 - genetics; Interleukin-13 - metabolism; Interleukin-4 - genetics; Interleukin-4 - metabolism; Interleukin-4 Receptor alpha Subunit - genetics; Interleukin-4 Receptor alpha Subunit - metabolism; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Knockout; Parasites; Receptors; Receptors, Interleukin-13 - genetics; Receptors, Interleukin-13 - metabolism; Rodents; Stat6 protein; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; T cell receptors; Transcription; Tumor necrosis factor-α; Vaccines; Vaccinia - genetics; Vaccinia - immunology; Vaccinia - metabolism; Vaccinia virus - immunology; Viruses; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0055788

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.