STAT3 determines IL-4 signalling outcomes in na\xefve T cells

Lachlan P Deimel,Sreeja Roy,Charani Ranasinghe,Zheyi Li

doi:10.1038/s41598-021-89860-7

Lachlan P Deimel, Sreeja Roy + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-89860-7

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Abstract

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+CD44lo–mid) 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.

Highlights

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
IL-4R⍺ expression profiles on both CD4 and CD8 T cells were evaluated by flow cytometry (Fig. 1a)
Our findings revealed that the IL-4-induced phosphorylation of STAT3 and STAT6 were linked to the T cell effector status (CD62L expression) (Fig. 4), similar to what was observed with IL-4R⍺ regulation (Fig. 2)

Summary

Introduction

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. Studies in our laboratory have shown that a pox viral vector-based prime-boost vaccine strategy that co-expresses HIV antigens together with an IL-4 receptor antagonist can drastically improve avidity, poly-functionality and cytotoxicity of mucosal and systemic HIV-specific CD4 and CD8 T cells, associated with protection in both mice and m acaques[10,13,14,15]. While this is a hopeful step towards establishing protective immunity against HIV-1, how different T cells govern and regulate their response to different IL-4 conditions at the molecular level still remains unclear. Recent viral vectorbased vaccine studies by Roy et al have revealed swift regulation of IL-13R⍺2 on lung conventional dendritic cells (cDCs), occurring in both an IL-13 concentration- and STAT3-dependent m anner[20]

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