Glucose represses dendritic cell-induced T cell responses

Simon J. Lawless; Nidhi Kedia-Mehta; Jessica F. Walls; Ryan McGarrigle; Orla Convery; Linda V Sinclair; Maria N. Navarro; James Murray; David K. Finlay

doi:10.1038/ncomms15620

Glucose represses dendritic cell-induced T cell responses

Simon J. Lawless, Nidhi Kedia-Mehta, Jessica F. Walls, Ryan McGarrigle, Orla Convery, Linda V Sinclair, Maria N. Navarro, James Murray, David K. Finlay (Lead / Corresponding author)

Cell Signalling and Immunology

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Abstract

Glucose and glycolysis are important for the proinflammatory functions of many immune cells, and depletion of glucose in pathological microenvironments is associated with defective immune responses. Here we show a contrasting function for glucose in dendritic cells (DCs), as glucose represses the proinflammatory output of LPS-stimulated DCs and inhibits DC-induced T-cell responses. A glucose-sensitive signal transduction circuit involving the mTOR complex 1 (mTORC1), HIF1α and inducible nitric oxide synthase (iNOS) coordinates DC metabolism and function to limit DC-stimulated T-cell responses. When multiple T cells interact with a DC, they compete for nutrients, which can limit glucose availability to the DCs. In such DCs, glucose-dependent signalling is inhibited, altering DC outputs and enhancing T-cell responses. These data reveal a mechanism by which T cells regulate the DC microenvironment to control DC-induced T-cell responses and indicate that glucose is an important signal for shaping immune responses.

Original language	English
Article number	15620
Pages (from-to)	1-14
Number of pages	14
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15620
Publication status	Published - 30 May 2017

Keywords

Dendritic cells
Nutrient signalling
T cells

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Final published version, 1.9 MBLicence: CC BY

Cite this

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title = "Glucose represses dendritic cell-induced T cell responses",

abstract = "Glucose and glycolysis are important for the proinflammatory functions of many immune cells, and depletion of glucose in pathological microenvironments is associated with defective immune responses. Here we show a contrasting function for glucose in dendritic cells (DCs), as glucose represses the proinflammatory output of LPS-stimulated DCs and inhibits DC-induced T-cell responses. A glucose-sensitive signal transduction circuit involving the mTOR complex 1 (mTORC1), HIF1α and inducible nitric oxide synthase (iNOS) coordinates DC metabolism and function to limit DC-stimulated T-cell responses. When multiple T cells interact with a DC, they compete for nutrients, which can limit glucose availability to the DCs. In such DCs, glucose-dependent signalling is inhibited, altering DC outputs and enhancing T-cell responses. These data reveal a mechanism by which T cells regulate the DC microenvironment to control DC-induced T-cell responses and indicate that glucose is an important signal for shaping immune responses.",

keywords = "Dendritic cells, Nutrient signalling, T cells",

author = "Lawless, {Simon J.} and Nidhi Kedia-Mehta and Walls, {Jessica F.} and Ryan McGarrigle and Orla Convery and Sinclair, {Linda V} and Navarro, {Maria N.} and James Murray and Finlay, {David K.}",

note = "This work was supported by funding from Science Foundation Ireland (13/CDA/2161) and Marie Sk{\l}odowska-Curie Actions (PCIG11-GA-2012-321603). S.J.L. was supported by a MolCellBio PhD scholarship funded by the Programme for Research in Third-Level Institutions (PRTLI). J.F.W was supported by a Wellcome Trust Studentship (106811/Z/15/Z).",

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AU - Lawless, Simon J.

AU - Kedia-Mehta, Nidhi

AU - Walls, Jessica F.

AU - McGarrigle, Ryan

AU - Convery, Orla

AU - Sinclair, Linda V

AU - Navarro, Maria N.

AU - Murray, James

AU - Finlay, David K.

N1 - This work was supported by funding from Science Foundation Ireland (13/CDA/2161) and Marie Skłodowska-Curie Actions (PCIG11-GA-2012-321603). S.J.L. was supported by a MolCellBio PhD scholarship funded by the Programme for Research in Third-Level Institutions (PRTLI). J.F.W was supported by a Wellcome Trust Studentship (106811/Z/15/Z).

PY - 2017/5/30

Y1 - 2017/5/30

N2 - Glucose and glycolysis are important for the proinflammatory functions of many immune cells, and depletion of glucose in pathological microenvironments is associated with defective immune responses. Here we show a contrasting function for glucose in dendritic cells (DCs), as glucose represses the proinflammatory output of LPS-stimulated DCs and inhibits DC-induced T-cell responses. A glucose-sensitive signal transduction circuit involving the mTOR complex 1 (mTORC1), HIF1α and inducible nitric oxide synthase (iNOS) coordinates DC metabolism and function to limit DC-stimulated T-cell responses. When multiple T cells interact with a DC, they compete for nutrients, which can limit glucose availability to the DCs. In such DCs, glucose-dependent signalling is inhibited, altering DC outputs and enhancing T-cell responses. These data reveal a mechanism by which T cells regulate the DC microenvironment to control DC-induced T-cell responses and indicate that glucose is an important signal for shaping immune responses.

AB - Glucose and glycolysis are important for the proinflammatory functions of many immune cells, and depletion of glucose in pathological microenvironments is associated with defective immune responses. Here we show a contrasting function for glucose in dendritic cells (DCs), as glucose represses the proinflammatory output of LPS-stimulated DCs and inhibits DC-induced T-cell responses. A glucose-sensitive signal transduction circuit involving the mTOR complex 1 (mTORC1), HIF1α and inducible nitric oxide synthase (iNOS) coordinates DC metabolism and function to limit DC-stimulated T-cell responses. When multiple T cells interact with a DC, they compete for nutrients, which can limit glucose availability to the DCs. In such DCs, glucose-dependent signalling is inhibited, altering DC outputs and enhancing T-cell responses. These data reveal a mechanism by which T cells regulate the DC microenvironment to control DC-induced T-cell responses and indicate that glucose is an important signal for shaping immune responses.

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KW - Nutrient signalling

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SP - 1

EP - 14

JO - Nature Communications

JF - Nature Communications

M1 - 15620

ER -

Glucose represses dendritic cell-induced T cell responses

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