Mitochondria Are Required for Antigen-Specific T Cell Activation through Reactive Oxygen Species Signaling

Laura A. Sena; Sha Li; Amit Jairaman; Murali Prakriya; Teresa Ezponda; David A. Hildeman; Chyung Ru Wang; Paul T. Schumacker; Jonathan D. Licht; Harris Perlman; Paul J. Bryce; Navdeep S. Chandel

doi:10.1016/j.immuni.2012.10.020

Mitochondria Are Required for Antigen-Specific T Cell Activation through Reactive Oxygen Species Signaling

Laura A. Sena, Sha Li, Amit Jairaman, Murali Prakriya, Teresa Ezponda, David A. Hildeman, Chyung Ru Wang, Paul T. Schumacker, Jonathan D. Licht, Harris Perlman, Paul J. Bryce, Navdeep S. Chandel^*

^*Corresponding author for this work

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

985 Scopus citations

Abstract

It is widely appreciated that T cells increase glycolytic flux during activation, but the role of mitochondrial flux is unclear. Here, we have shown that mitochondrial metabolism in the absence of glucose metabolism is sufficient to support interleukin-2 (IL-2) induction. Furthermore, we used mice with reduced mitochondrial reactive oxygen species (mROS) production in T cells (T-Uqcrfs^-/- mice) to show that mitochondria are required for T cell activation to produce mROS for activation of nuclear factor of activated T cells (NFAT) and subsequent IL-2 induction. These mice could not induce antigen-specific expansion of T cells in vivo, but Uqcrfs1^-/- T cells retained the ability to proliferate in vivo under lymphopenic conditions. This suggests that Uqcrfs1^-/- T cells were not lacking bioenergetically but rather lacked specific ROS-dependent signaling events needed for antigen-specific expansion. Thus, mitochondrial metabolism is a critical component of T cell activation through the production of complex III ROS.

Original language	English (US)
Pages (from-to)	225-236
Number of pages	12
Journal	Immunity
Volume	38
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2012.10.020
State	Published - Feb 21 2013

Funding

We thank Balaraman Kalyanaraman and Joy Joseph for their kind contribution of mitovitamin E. This work was supported by National Institute of Health grants F30ES019815 (L.A.S.), T32-HL76139 (L.A.S.), 5P01HL071643 (N.S.C.), R01-AI076456 (P.B.), NS047599 (A.J.), R01-AI057753 (D.A.H.), R01-AI040310 (C.W.), RR025355 (P.T.S.), HL35440 (P.T.S.), AR050250 (H.P.), AR054796 (H.P.), AI092490 (H.P.), and HL108795 (H.P.) and funds provided by Northwestern University, Feinberg School of Medicine to Harris Perlman.

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2012.10.020

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@article{da30ccdb9f174ec1ae6f4a7c249896bc,

title = "Mitochondria Are Required for Antigen-Specific T Cell Activation through Reactive Oxygen Species Signaling",

abstract = "It is widely appreciated that T cells increase glycolytic flux during activation, but the role of mitochondrial flux is unclear. Here, we have shown that mitochondrial metabolism in the absence of glucose metabolism is sufficient to support interleukin-2 (IL-2) induction. Furthermore, we used mice with reduced mitochondrial reactive oxygen species (mROS) production in T cells (T-Uqcrfs-/- mice) to show that mitochondria are required for T cell activation to produce mROS for activation of nuclear factor of activated T cells (NFAT) and subsequent IL-2 induction. These mice could not induce antigen-specific expansion of T cells in vivo, but Uqcrfs1-/- T cells retained the ability to proliferate in vivo under lymphopenic conditions. This suggests that Uqcrfs1-/- T cells were not lacking bioenergetically but rather lacked specific ROS-dependent signaling events needed for antigen-specific expansion. Thus, mitochondrial metabolism is a critical component of T cell activation through the production of complex III ROS.",

author = "Sena, {Laura A.} and Sha Li and Amit Jairaman and Murali Prakriya and Teresa Ezponda and Hildeman, {David A.} and Wang, {Chyung Ru} and Schumacker, {Paul T.} and Licht, {Jonathan D.} and Harris Perlman and Bryce, {Paul J.} and Chandel, {Navdeep S.}",

note = "Funding Information: We thank Balaraman Kalyanaraman and Joy Joseph for their kind contribution of mitovitamin E. This work was supported by National Institute of Health grants F30ES019815 (L.A.S.), T32-HL76139 (L.A.S.), 5P01HL071643 (N.S.C.), R01-AI076456 (P.B.), NS047599 (A.J.), R01-AI057753 (D.A.H.), R01-AI040310 (C.W.), RR025355 (P.T.S.), HL35440 (P.T.S.), AR050250 (H.P.), AR054796 (H.P.), AI092490 (H.P.), and HL108795 (H.P.) and funds provided by Northwestern University, Feinberg School of Medicine to Harris Perlman. ",

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AU - Sena, Laura A.

AU - Li, Sha

AU - Jairaman, Amit

AU - Prakriya, Murali

AU - Ezponda, Teresa

AU - Hildeman, David A.

AU - Wang, Chyung Ru

AU - Schumacker, Paul T.

AU - Licht, Jonathan D.

AU - Perlman, Harris

AU - Bryce, Paul J.

AU - Chandel, Navdeep S.

N1 - Funding Information: We thank Balaraman Kalyanaraman and Joy Joseph for their kind contribution of mitovitamin E. This work was supported by National Institute of Health grants F30ES019815 (L.A.S.), T32-HL76139 (L.A.S.), 5P01HL071643 (N.S.C.), R01-AI076456 (P.B.), NS047599 (A.J.), R01-AI057753 (D.A.H.), R01-AI040310 (C.W.), RR025355 (P.T.S.), HL35440 (P.T.S.), AR050250 (H.P.), AR054796 (H.P.), AI092490 (H.P.), and HL108795 (H.P.) and funds provided by Northwestern University, Feinberg School of Medicine to Harris Perlman.

PY - 2013/2/21

Y1 - 2013/2/21

N2 - It is widely appreciated that T cells increase glycolytic flux during activation, but the role of mitochondrial flux is unclear. Here, we have shown that mitochondrial metabolism in the absence of glucose metabolism is sufficient to support interleukin-2 (IL-2) induction. Furthermore, we used mice with reduced mitochondrial reactive oxygen species (mROS) production in T cells (T-Uqcrfs-/- mice) to show that mitochondria are required for T cell activation to produce mROS for activation of nuclear factor of activated T cells (NFAT) and subsequent IL-2 induction. These mice could not induce antigen-specific expansion of T cells in vivo, but Uqcrfs1-/- T cells retained the ability to proliferate in vivo under lymphopenic conditions. This suggests that Uqcrfs1-/- T cells were not lacking bioenergetically but rather lacked specific ROS-dependent signaling events needed for antigen-specific expansion. Thus, mitochondrial metabolism is a critical component of T cell activation through the production of complex III ROS.

AB - It is widely appreciated that T cells increase glycolytic flux during activation, but the role of mitochondrial flux is unclear. Here, we have shown that mitochondrial metabolism in the absence of glucose metabolism is sufficient to support interleukin-2 (IL-2) induction. Furthermore, we used mice with reduced mitochondrial reactive oxygen species (mROS) production in T cells (T-Uqcrfs-/- mice) to show that mitochondria are required for T cell activation to produce mROS for activation of nuclear factor of activated T cells (NFAT) and subsequent IL-2 induction. These mice could not induce antigen-specific expansion of T cells in vivo, but Uqcrfs1-/- T cells retained the ability to proliferate in vivo under lymphopenic conditions. This suggests that Uqcrfs1-/- T cells were not lacking bioenergetically but rather lacked specific ROS-dependent signaling events needed for antigen-specific expansion. Thus, mitochondrial metabolism is a critical component of T cell activation through the production of complex III ROS.

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ER -

Mitochondria Are Required for Antigen-Specific T Cell Activation through Reactive Oxygen Species Signaling

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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