STAT3 determines IL-4 signalling outcomes in naïve T cells

• Published in: Scientific reports Vol. 11; no. 1; p. 10495
• Main Authors: Deimel, Lachlan P, Li, Zheyi, Roy, Sreeja, Ranasinghe, Charani
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.05.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Avidity; Biomarkers - metabolism; CD4 antigen; CD8 antigen; Cytotoxicity; Dendritic cells; Female; Interferon; Interleukin 13; Interleukin 4; Interleukin-4 - metabolism; L-selectin; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred BALB C; Phosphorylation; Receptors, Interleukin-4 - metabolism; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - physiology; Stat6 protein; STAT6 Transcription Factor - metabolism; T-Lymphocytes - metabolism; Transcription factors; Transforming growth factor-b1; Vaccines
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-89860-7

IL-4 production is associated with low-avidity, poorly cytotoxic T cell induction that contributes to viral immune evasion and the failure of T cell-based vaccines. Yet, the precise mechanisms that regulate IL-4 signalling in T cells remain elusive. Mounting evidence indicates that cells can dynamically alter their IL-4/IL-13 receptor signature to modulate downstream immune outcomes upon pathogen encounter. Here, we describe how naïve (CD62L CD44 ) CD4 and CD8 T cells distinctly engage both STAT6 and STAT3 in response to IL-4. We further show that IL-4R⍺ expression is both time- and IL-4 concentration-dependent. Remarkably, our findings reveal that STAT3 inhibition can ablate IL-4R⍺ and affect transcriptional expression of other Stat and Jak family members. By extension, the loss of STAT3 lead to aberrant STAT6 phosphorylation, revealing an inter-regulatory relationship between the two transcription factors. Moreover, IL-4 stimulation down-regulated TGF-β1 and IFN-γR1 expression on naïve T cells, possibly signifying the broad regulatory implications of IL-4 in conditioning lineage commitment decisions during early infection. Surprisingly, naïve T cells were unresponsive to IL-13 stimulation, unlike dendritic cells. Collectively, these findings could be exploited to inform more efficacious vaccines, as well as design treatments against IL-4/IL-13-associated disease conditions.