Active Tonic mTORC1 Signals Shape Baseline Translation in Naive T Cells
Myers, Darienne R.; Norlin, Emilia; Vercoulen, Yvonne; Roose, Jeroen P.
(2019) Cell Reports, volume 27, issue 6, pp. 1858 - 1874.e6
(Article)
Abstract
Naive CD4 + T cells are an example of dynamic cell homeostasis: T cells need to avoid autoreactivity while constantly seeing self-peptides, yet they must be primed to react to foreign antigens during infection. The instructive signals that balance this primed yet quiescent state are unknown. Interactions with self-peptides result
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in membrane-proximal, tonic signals in resting T cells. Here we reveal selective and robust tonic mTORC1 signals in CD4 + T cells that influence T cell fate decisions. We find that the Ras exchange factor Rasgrp1 is necessary to generate tonic mTORC1 signals. Genome-wide ribosome profiling of resting, primary CD4 + T cells uncovers a baseline translational landscape rich in mTOR targets linked to mitochondria, oxidative phosphorylation, and splicing. Aberrantly increased tonic mTORC1 signals from a Rasgrp1 Anaef allele result in immunopathology with spontaneous appearance of T peripheral helper cells, follicular helper T cells, and anti-nuclear antibodies that are preceded by subtle alterations in the translational landscape. Myers et al. evaluate a mouse model of autoimmunity, Rasgrp1 Anaef . They find that T cells with the Rasgrp1 Anaef allele exhibit altered signaling from Rasgrp1 to the mTORC1 pathway in the basal state. They show that increased basal Rasgrp1 Anaef -mTORC1 signals lead to an altered translational landscape in T cells and immunopathology.
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Keywords: Anaef, autoimmunity, CD44, CD5, mRNA translation, mTOR, naive T cell, Rasgrp1, ribosome profiling, tonic signaling, General Biochemistry,Genetics and Molecular Biology
ISSN: 2211-1247
Publisher: Cell Press
Note: Funding Information: We thank all members of the Roose lab for helpful discussions and Drs. Richard Locksley, Stephen Floor, and Roberto Zoncu for critical reading of the manuscript. We thank the University of California, San Francisco (UCSF), Parnassus Flow Cytometry Core for assistance with cell sorting (NIH grant P30 DK063720); the UCSF Functional Genomics Core (David Erle, Andrea Barczak, Walter Eckalbar, and Matthew Aber) for RNA-seq library preparation; the UCSF Center for Advanced Technology for sequencing; Max Horlbeck for assistance with bioinformatics; and Elizabeth Costa, Dan Santos, Kristen Lynch, and Steve Rosen for helpful discussions on ribosome profiling, splicing, and adhesion. We thank Zoltan Laszik for kidney evaluations, Peter Werba for bioinformatics infrastructure, and Anna Hupalowska for illustrations. These studies were supported by grants from the NSF-GRFP (1650113 to D.R.M.), the Marie Curie IOF (PIOF-GA-2012-328666 to Y.V.), and the NIH-NIAID (R01-AI104789 and P01-AI091580 to J.P.R.). E.N. and Y.V. performed experiments and analyzed data. D.R.M. performed experiments, analyzed data, and together with J.P.R. conceived the study and wrote the manuscript. J.P.R. is a co-founder and scientific advisor of Seal Biosciences, Inc. and a member of the scientific advisory committee for the Mark Foundation for Cancer Research. Funding Information: We thank all members of the Roose lab for helpful discussions and Drs. Richard Locksley, Stephen Floor, and Roberto Zoncu for critical reading of the manuscript. We thank the University of California, San Francisco (UCSF), Parnassus Flow Cytometry Core for assistance with cell sorting (NIH grant P30 DK063720); the UCSF Functional Genomics Core (David Erle, Andrea Barczak, Walter Eckalbar, and Matthew Aber)for RNA-seq library preparation; the UCSF Center for Advanced Technology for sequencing; Max Horlbeck for assistance with bioinformatics; and Elizabeth Costa, Dan Santos, Kristen Lynch, and Steve Rosen for helpful discussions on ribosome profiling, splicing, and adhesion. We thank Zoltan Laszik for kidney evaluations, Peter Werba for bioinformatics infrastructure, and Anna Hupalowska for illustrations. These studies were supported by grants from the NSF-GRFP (1650113 to D.R.M.), the Marie Curie IOF (PIOF-GA-2012-328666 to Y.V.), and the NIH-NIAID (R01-AI104789 and P01-AI091580 to J.P.R.). E.N. and Y.V. performed experiments and analyzed data. D.R.M. performed experiments, analyzed data, and together with J.P.R. conceived the study and wrote the manuscript. J.P.R. is a co-founder and scientific advisor of Seal Biosciences, Inc. and a member of the scientific advisory committee for the Mark Foundation for Cancer Research. Funding Information: We thank all members of the Roose lab for helpful discussions and Drs. Richard Locksley, Stephen Floor, and Roberto Zoncu for critical reading of the manuscript. We thank the University of California, San Francisco (UCSF), Parnassus Flow Cytometry Core for assistance with cell sorting ( NIH grant P30 DK063720 ); the UCSF Functional Genomics Core (David Erle, Andrea Barczak, Walter Eckalbar, and Matthew Aber) for RNA-seq library preparation; the UCSF Center for Advanced Technology for sequencing; Max Horlbeck for assistance with bioinformatics; and Elizabeth Costa, Dan Santos, Kristen Lynch, and Steve Rosen for helpful discussions on ribosome profiling, splicing, and adhesion. We thank Zoltan Laszik for kidney evaluations, Peter Werba for bioinformatics infrastructure, and Anna Hupalowska for illustrations. These studies were supported by grants from the NSF-GRFP ( 1650113 to D.R.M.), the Marie Curie IOF ( PIOF-GA-2012-328666 to Y.V.), and the NIH-NIAID ( R01-AI104789 and P01-AI091580 to J.P.R.). Publisher Copyright: © 2019 The Author(s)
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