STAT3 determines IL-4 signalling outcomes in naïve T cells

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 ca...

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Autores principales:	Lachlan P. Deimel, Zheyi Li, Sreeja Roy, Charani Ranasinghe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9d3a69cae7d44875ab35f73cf32c12c7
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spelling	oai:doaj.org-article:9d3a69cae7d44875ab35f73cf32c12c72021-12-02T15:45:15ZSTAT3 determines IL-4 signalling outcomes in naïve T cells10.1038/s41598-021-89860-72045-2322https://doaj.org/article/9d3a69cae7d44875ab35f73cf32c12c72021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89860-7https://doaj.org/toc/2045-2322Abstract 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.Lachlan P. DeimelZheyi LiSreeja RoyCharani RanasingheNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lachlan P. Deimel Zheyi Li Sreeja Roy Charani Ranasinghe STAT3 determines IL-4 signalling outcomes in naïve T cells
description	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.
format	article
author	Lachlan P. Deimel Zheyi Li Sreeja Roy Charani Ranasinghe
author_facet	Lachlan P. Deimel Zheyi Li Sreeja Roy Charani Ranasinghe
author_sort	Lachlan P. Deimel
title	STAT3 determines IL-4 signalling outcomes in naïve T cells
title_short	STAT3 determines IL-4 signalling outcomes in naïve T cells
title_full	STAT3 determines IL-4 signalling outcomes in naïve T cells
title_fullStr	STAT3 determines IL-4 signalling outcomes in naïve T cells
title_full_unstemmed	STAT3 determines IL-4 signalling outcomes in naïve T cells
title_sort	stat3 determines il-4 signalling outcomes in naïve t cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9d3a69cae7d44875ab35f73cf32c12c7
work_keys_str_mv	AT lachlanpdeimel stat3determinesil4signallingoutcomesinnaivetcells AT zheyili stat3determinesil4signallingoutcomesinnaivetcells AT sreejaroy stat3determinesil4signallingoutcomesinnaivetcells AT charaniranasinghe stat3determinesil4signallingoutcomesinnaivetcells
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STAT3 determines IL-4 signalling outcomes in naïve T cells

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