Quantitative analysis of T cell proteomes and environmental sensors during T cell differentiation

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Abstract

Quantitative mass spectrometry reveals how CD4 + and CD8 + T cells restructure proteomes in response to antigen and mammalian target of rapamycin complex 1 (mTORC1). Analysis of copy numbers per cell of >9,000 proteins provides new understanding of T cell phenotypes, exposing the metabolic and protein synthesis machinery and environmental sensors that shape T cell fate. We reveal that lymphocyte environment sensing is controlled by immune activation, and that CD4 + and CD8 + T cells differ in their intrinsic nutrient transport and biosynthetic capacity. Our data also reveal shared and divergent outcomes of mTORC1 inhibition in naïve versus effector T cells: mTORC1 inhibition impaired cell cycle progression in activated naïve cells, but not effector cells, whereas metabolism was consistently impacted in both populations. This study provides a comprehensive map of naïve and effector T cell proteomes, and a resource for exploring and understanding T cell phenotypes and cell context effects of mTORC1.

Original languageEnglish
Pages (from-to)1542-1554
Number of pages13
JournalNature Immunology
Volume20
Issue number11
DOIs
Publication statusPublished - 7 Oct 2019

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Proteome
Cell Differentiation
T-Lymphocytes
Phenotype
Mass Spectrometry
Cell Cycle
Proteins
Cell Count
Lymphocytes
Antigens
Food
mechanistic target of rapamycin complex 1
Population

Cite this

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title = "Quantitative analysis of T cell proteomes and environmental sensors during T cell differentiation",
abstract = "Quantitative mass spectrometry reveals how CD4 + and CD8 + T cells restructure proteomes in response to antigen and mammalian target of rapamycin complex 1 (mTORC1). Analysis of copy numbers per cell of >9,000 proteins provides new understanding of T cell phenotypes, exposing the metabolic and protein synthesis machinery and environmental sensors that shape T cell fate. We reveal that lymphocyte environment sensing is controlled by immune activation, and that CD4 + and CD8 + T cells differ in their intrinsic nutrient transport and biosynthetic capacity. Our data also reveal shared and divergent outcomes of mTORC1 inhibition in na{\"i}ve versus effector T cells: mTORC1 inhibition impaired cell cycle progression in activated na{\"i}ve cells, but not effector cells, whereas metabolism was consistently impacted in both populations. This study provides a comprehensive map of na{\"i}ve and effector T cell proteomes, and a resource for exploring and understanding T cell phenotypes and cell context effects of mTORC1.",
author = "Howden, {Andy J. M.} and Hukelmann, {Jens L.} and Alejandro Brenes and Laura Spinelli and Sinclair, {Linda V.} and Lamond, {Angus I.} and Cantrell, {Doreen A.}",
note = "This research was supported by a Wellcome Trust Principal Research Fellowship to D.A.C. (205023/Z/16/Z), a Wellcome Trust Strategic Award to D.A.C. and A.I.L. (105024/Z/14/Z) and a Wellcome Trust Equipment Award to D.A.C. (202950/Z/16/Z).",
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AU - Howden, Andy J. M.

AU - Hukelmann, Jens L.

AU - Brenes, Alejandro

AU - Spinelli, Laura

AU - Sinclair, Linda V.

AU - Lamond, Angus I.

AU - Cantrell, Doreen A.

N1 - This research was supported by a Wellcome Trust Principal Research Fellowship to D.A.C. (205023/Z/16/Z), a Wellcome Trust Strategic Award to D.A.C. and A.I.L. (105024/Z/14/Z) and a Wellcome Trust Equipment Award to D.A.C. (202950/Z/16/Z).

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AB - Quantitative mass spectrometry reveals how CD4 + and CD8 + T cells restructure proteomes in response to antigen and mammalian target of rapamycin complex 1 (mTORC1). Analysis of copy numbers per cell of >9,000 proteins provides new understanding of T cell phenotypes, exposing the metabolic and protein synthesis machinery and environmental sensors that shape T cell fate. We reveal that lymphocyte environment sensing is controlled by immune activation, and that CD4 + and CD8 + T cells differ in their intrinsic nutrient transport and biosynthetic capacity. Our data also reveal shared and divergent outcomes of mTORC1 inhibition in naïve versus effector T cells: mTORC1 inhibition impaired cell cycle progression in activated naïve cells, but not effector cells, whereas metabolism was consistently impacted in both populations. This study provides a comprehensive map of naïve and effector T cell proteomes, and a resource for exploring and understanding T cell phenotypes and cell context effects of mTORC1.

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