The eIF4EBP-eIF4E axis regulates CD4+ T cell differentiation through modulation of T cell activation and metabolism

Roman Istomine; Tho Alfakar Al-Aubodah; Fernando Alvarez; Jacob A. Smith; Carston Wagner; Ciriaco A. Piccirillo

doi:10.1016/j.isci.2023.106683

The eIF4EBP-eIF4E axis regulates CD4⁺ T cell differentiation through modulation of T cell activation and metabolism

Roman Istomine, Tho Alfakar Al-Aubodah, Fernando Alvarez, Jacob A. Smith, Carston Wagner, Ciriaco A. Piccirillo

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

CD4⁺ T cells are critical for adaptive immunity, differentiating into distinct effector and regulatory subsets. Although the transcriptional programs underlying their differentiation are known, recent research has highlighted the importance of mRNA translation in determining protein abundance. We previously conducted genome-wide analysis of translation in CD4⁺ T cells revealing distinct translational signatures distinguishing these subsets, identifying eIF4E as a central differentially translated transcript. As eIF4E is vital for eukaryotic translation, we examined how altered eIF4E activity affected T cell function using mice lacking eIF4E-binding proteins (BP^-/-). BP^-/- effector T cells showed elevated Th1 responses ex vivo and upon viral challenge with enhanced Th1 differentiation observed in vitro. This was accompanied by increased TCR activation and elevated glycolytic activity. This study highlights how regulating T cell-intrinsic eIF4E activity can influence T cell activation and differentiation, suggesting the eIF4EBP-eIF4E axis as a potential therapeutic target for controlling aberrant T cell responses.

Original language	English (US)
Article number	106683
Journal	iScience
Volume	26
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2023.106683
State	Published - May 19 2023

Bibliographical note

Funding Information:
This work was funded by a Canadian Institutes of Health Research (CIHR) operating grant (PJT-148821) awarded to C.A.P. We thank the RI-MUHC Immunophenotyping Platform for their excellent cell sorting service. We also thank the RI-MUHC Proteomics Platform for their help in the design and execution of the proteomic analyses. Conceptualization: R.I. and C.A.P.; Investigation: R.I. T.A. and F.A.; Formal Analysis: R.I. and C.A.P.; Methodology: R.I. T.A. and F.A.; Writing – Original Draft: R.I. and C.A.P.; Writing – Review & Editing: R.I. T.A. F.A. and C.A.P.; Funding Acquisition: C.A.P.; Resources: J.A.S. C.W. and C.A.P. The authors declare no competing interests.

Funding Information:
This work was funded by a Canadian Institutes of Health Research (CIHR) operating grant ( PJT-148821 ) awarded to C.A.P. We thank the RI-MUHC Immunophenotyping Platform for their excellent cell sorting service. We also thank the RI-MUHC Proteomics Platform for their help in the design and execution of the proteomic analyses.

Publisher Copyright:
© 2023

Keywords

Biological sciences
Immunology
Molecular biology
Proteomics

PubMed: MeSH publication types

Journal Article

Publisher link

10.1016/j.isci.2023.106683

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title = "The eIF4EBP-eIF4E axis regulates CD4+ T cell differentiation through modulation of T cell activation and metabolism",

abstract = "CD4+ T cells are critical for adaptive immunity, differentiating into distinct effector and regulatory subsets. Although the transcriptional programs underlying their differentiation are known, recent research has highlighted the importance of mRNA translation in determining protein abundance. We previously conducted genome-wide analysis of translation in CD4+ T cells revealing distinct translational signatures distinguishing these subsets, identifying eIF4E as a central differentially translated transcript. As eIF4E is vital for eukaryotic translation, we examined how altered eIF4E activity affected T cell function using mice lacking eIF4E-binding proteins (BP-/-). BP-/- effector T cells showed elevated Th1 responses ex vivo and upon viral challenge with enhanced Th1 differentiation observed in vitro. This was accompanied by increased TCR activation and elevated glycolytic activity. This study highlights how regulating T cell-intrinsic eIF4E activity can influence T cell activation and differentiation, suggesting the eIF4EBP-eIF4E axis as a potential therapeutic target for controlling aberrant T cell responses.",

keywords = "Biological sciences, Immunology, Molecular biology, Proteomics",

author = "Roman Istomine and Al-Aubodah, {Tho Alfakar} and Fernando Alvarez and Smith, {Jacob A.} and Carston Wagner and Piccirillo, {Ciriaco A.}",

note = "Funding Information: This work was funded by a Canadian Institutes of Health Research (CIHR) operating grant (PJT-148821) awarded to C.A.P. We thank the RI-MUHC Immunophenotyping Platform for their excellent cell sorting service. We also thank the RI-MUHC Proteomics Platform for their help in the design and execution of the proteomic analyses. Conceptualization: R.I. and C.A.P.; Investigation: R.I. T.A. and F.A.; Formal Analysis: R.I. and C.A.P.; Methodology: R.I. T.A. and F.A.; Writing – Original Draft: R.I. and C.A.P.; Writing – Review & Editing: R.I. T.A. F.A. and C.A.P.; Funding Acquisition: C.A.P.; Resources: J.A.S. C.W. and C.A.P. The authors declare no competing interests. Funding Information: This work was funded by a Canadian Institutes of Health Research (CIHR) operating grant ( PJT-148821 ) awarded to C.A.P. We thank the RI-MUHC Immunophenotyping Platform for their excellent cell sorting service. We also thank the RI-MUHC Proteomics Platform for their help in the design and execution of the proteomic analyses. Publisher Copyright: {\textcopyright} 2023",

year = "2023",

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AU - Istomine, Roman

AU - Al-Aubodah, Tho Alfakar

AU - Alvarez, Fernando

AU - Smith, Jacob A.

AU - Wagner, Carston

AU - Piccirillo, Ciriaco A.

N1 - Funding Information: This work was funded by a Canadian Institutes of Health Research (CIHR) operating grant (PJT-148821) awarded to C.A.P. We thank the RI-MUHC Immunophenotyping Platform for their excellent cell sorting service. We also thank the RI-MUHC Proteomics Platform for their help in the design and execution of the proteomic analyses. Conceptualization: R.I. and C.A.P.; Investigation: R.I. T.A. and F.A.; Formal Analysis: R.I. and C.A.P.; Methodology: R.I. T.A. and F.A.; Writing – Original Draft: R.I. and C.A.P.; Writing – Review & Editing: R.I. T.A. F.A. and C.A.P.; Funding Acquisition: C.A.P.; Resources: J.A.S. C.W. and C.A.P. The authors declare no competing interests. Funding Information: This work was funded by a Canadian Institutes of Health Research (CIHR) operating grant ( PJT-148821 ) awarded to C.A.P. We thank the RI-MUHC Immunophenotyping Platform for their excellent cell sorting service. We also thank the RI-MUHC Proteomics Platform for their help in the design and execution of the proteomic analyses. Publisher Copyright: © 2023

PY - 2023/5/19

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N2 - CD4+ T cells are critical for adaptive immunity, differentiating into distinct effector and regulatory subsets. Although the transcriptional programs underlying their differentiation are known, recent research has highlighted the importance of mRNA translation in determining protein abundance. We previously conducted genome-wide analysis of translation in CD4+ T cells revealing distinct translational signatures distinguishing these subsets, identifying eIF4E as a central differentially translated transcript. As eIF4E is vital for eukaryotic translation, we examined how altered eIF4E activity affected T cell function using mice lacking eIF4E-binding proteins (BP-/-). BP-/- effector T cells showed elevated Th1 responses ex vivo and upon viral challenge with enhanced Th1 differentiation observed in vitro. This was accompanied by increased TCR activation and elevated glycolytic activity. This study highlights how regulating T cell-intrinsic eIF4E activity can influence T cell activation and differentiation, suggesting the eIF4EBP-eIF4E axis as a potential therapeutic target for controlling aberrant T cell responses.

AB - CD4+ T cells are critical for adaptive immunity, differentiating into distinct effector and regulatory subsets. Although the transcriptional programs underlying their differentiation are known, recent research has highlighted the importance of mRNA translation in determining protein abundance. We previously conducted genome-wide analysis of translation in CD4+ T cells revealing distinct translational signatures distinguishing these subsets, identifying eIF4E as a central differentially translated transcript. As eIF4E is vital for eukaryotic translation, we examined how altered eIF4E activity affected T cell function using mice lacking eIF4E-binding proteins (BP-/-). BP-/- effector T cells showed elevated Th1 responses ex vivo and upon viral challenge with enhanced Th1 differentiation observed in vitro. This was accompanied by increased TCR activation and elevated glycolytic activity. This study highlights how regulating T cell-intrinsic eIF4E activity can influence T cell activation and differentiation, suggesting the eIF4EBP-eIF4E axis as a potential therapeutic target for controlling aberrant T cell responses.

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KW - Molecular biology

KW - Proteomics

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