Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

Marc O. Johnson; Melissa M. Wolf; Matthew Z. Madden; Gabriela Andrejeva; Ayaka Sugiura; Diana C. Contreras; Damian Maseda; Maria V. Liberti; Katelyn Paz; Rigel J. Kishton; Matthew E. Johnson; Aguirre A. de Cubas; Pingsheng Wu; Gongbo Li; Yongliang Zhang; Dawn C. Newcomb; Andrew D. Wells; Nicholas P. Restifo; W. Kimryn Rathmell; Jason W. Locasale; Marco L. Davila; Bruce R. Blazar; Jeffrey C. Rathmell

doi:10.1016/j.cell.2018.10.001

Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

Marc O. Johnson, Melissa M. Wolf, Matthew Z. Madden, Gabriela Andrejeva, Ayaka Sugiura, Diana C. Contreras, Damian Maseda, Maria V. Liberti, Katelyn Paz, Rigel J. Kishton, Matthew E. Johnson, Aguirre A. de Cubas, Pingsheng Wu, Gongbo Li, Yongliang Zhang, Dawn C. Newcomb, Andrew D. Wells, Nicholas P. Restifo, W. Kimryn Rathmell, Jason W. LocasaleMarco L. Davila, Bruce R. Blazar, Jeffrey C. Rathmell

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285 Scopus citations

Abstract

Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

Original language	English (US)
Pages (from-to)	1780-1795.e19
Journal	Cell
Volume	175
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2018.10.001
State	Published - Dec 13 2018

Bibliographical note

Funding Information:
We thank members of the Rathmell lab and H. Hu (University of Alabama, Birmingham) for providing MSCV-PIK3IP-IRES-Thy1.1 and control retroviral constructs, T. Dileepan and M.K. Jenkins (University of Minnesota) for providing reagents for 2W immunization and tetramer staining, and J. Cools (VIB) for providing pMx-U6 plasmids. Some CB839 for in vitro studies was generously provided by Calithera Biosciences. This research was funded by the National Institutes of Health R01 HL136664 (J.C.R.), R01 DK105550 (J.C.R.), R01 CA217987 (J.C.R., W.K.R.), R01CA193256 (J.W.L.), and P30CA01423 (J.W.L.).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

T cells
chromatin
glutaminase
glutamine
mTOR
metabolism

Publisher link

10.1016/j.cell.2018.10.001

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361668

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Johnson, M. O., Wolf, M. M., Madden, M. Z., Andrejeva, G., Sugiura, A., Contreras, D. C., Maseda, D., Liberti, M. V., Paz, K., Kishton, R. J., Johnson, M. E., de Cubas, A. A., Wu, P., Li, G., Zhang, Y., Newcomb, D. C., Wells, A. D., Restifo, N. P., Rathmell, W. K., ... Rathmell, J. C. (2018). Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism. Cell, 175(7), 1780-1795.e19. https://doi.org/10.1016/j.cell.2018.10.001

Johnson, MO, Wolf, MM, Madden, MZ, Andrejeva, G, Sugiura, A, Contreras, DC, Maseda, D, Liberti, MV, Paz, K, Kishton, RJ, Johnson, ME, de Cubas, AA, Wu, P, Li, G, Zhang, Y, Newcomb, DC, Wells, AD, Restifo, NP, Rathmell, WK, Locasale, JW, Davila, ML, Blazar, BR & Rathmell, JC 2018, 'Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism', Cell, vol. 175, no. 7, pp. 1780-1795.e19. https://doi.org/10.1016/j.cell.2018.10.001

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title = "Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism",

abstract = "Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.",

keywords = "T cells, chromatin, glutaminase, glutamine, mTOR, metabolism",

author = "Johnson, {Marc O.} and Wolf, {Melissa M.} and Madden, {Matthew Z.} and Gabriela Andrejeva and Ayaka Sugiura and Contreras, {Diana C.} and Damian Maseda and Liberti, {Maria V.} and Katelyn Paz and Kishton, {Rigel J.} and Johnson, {Matthew E.} and {de Cubas}, {Aguirre A.} and Pingsheng Wu and Gongbo Li and Yongliang Zhang and Newcomb, {Dawn C.} and Wells, {Andrew D.} and Restifo, {Nicholas P.} and Rathmell, {W. Kimryn} and Locasale, {Jason W.} and Davila, {Marco L.} and Blazar, {Bruce R.} and Rathmell, {Jeffrey C.}",

note = "Funding Information: We thank members of the Rathmell lab and H. Hu (University of Alabama, Birmingham) for providing MSCV-PIK3IP-IRES-Thy1.1 and control retroviral constructs, T. Dileepan and M.K. Jenkins (University of Minnesota) for providing reagents for 2W immunization and tetramer staining, and J. Cools (VIB) for providing pMx-U6 plasmids. Some CB839 for in vitro studies was generously provided by Calithera Biosciences. This research was funded by the National Institutes of Health R01 HL136664 (J.C.R.), R01 DK105550 (J.C.R.), R01 CA217987 (J.C.R., W.K.R.), R01CA193256 (J.W.L.), and P30CA01423 (J.W.L.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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doi = "10.1016/j.cell.2018.10.001",

language = "English (US)",

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T1 - Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

AU - Johnson, Marc O.

AU - Wolf, Melissa M.

AU - Madden, Matthew Z.

AU - Andrejeva, Gabriela

AU - Sugiura, Ayaka

AU - Contreras, Diana C.

AU - Maseda, Damian

AU - Liberti, Maria V.

AU - Paz, Katelyn

AU - Kishton, Rigel J.

AU - Johnson, Matthew E.

AU - de Cubas, Aguirre A.

AU - Wu, Pingsheng

AU - Li, Gongbo

AU - Zhang, Yongliang

AU - Newcomb, Dawn C.

AU - Wells, Andrew D.

AU - Restifo, Nicholas P.

AU - Rathmell, W. Kimryn

AU - Locasale, Jason W.

AU - Davila, Marco L.

AU - Blazar, Bruce R.

AU - Rathmell, Jeffrey C.

N1 - Funding Information: We thank members of the Rathmell lab and H. Hu (University of Alabama, Birmingham) for providing MSCV-PIK3IP-IRES-Thy1.1 and control retroviral constructs, T. Dileepan and M.K. Jenkins (University of Minnesota) for providing reagents for 2W immunization and tetramer staining, and J. Cools (VIB) for providing pMx-U6 plasmids. Some CB839 for in vitro studies was generously provided by Calithera Biosciences. This research was funded by the National Institutes of Health R01 HL136664 (J.C.R.), R01 DK105550 (J.C.R.), R01 CA217987 (J.C.R., W.K.R.), R01CA193256 (J.W.L.), and P30CA01423 (J.W.L.). Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/12/13

Y1 - 2018/12/13

N2 - Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

AB - Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

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KW - chromatin

KW - glutaminase

KW - glutamine

KW - mTOR

KW - metabolism

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ER -

Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism

Abstract

Bibliographical note

Keywords

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