Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

Martin Kolev; Sarah Dimeloe; Gaelle Le Friec; Alexander Navarini; Giuseppina Arbore; Giovanni A. Povoleri; Marco Fischer; Réka Belle; Jordan Loeliger; Leyla Develioglu; Glenn R. Bantug; Julie Watson; Lionel Couzi; Behdad Afzali; Paul Lavender; Christoph Hess; Claudia Kemper

doi:10.1016/j.immuni.2015.05.024

Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

Martin Kolev, Sarah Dimeloe, Gaelle Le Friec, Alexander Navarini, Giuseppina Arbore, Giovanni A. Povoleri, Marco Fischer, Réka Belle, Jordan Loeliger, Leyla Develioglu, Glenn R. Bantug, Julie Watson, Lionel Couzi, Behdad Afzali, Paul Lavender, Christoph Hess^*, Claudia Kemper

^*Corresponding author for this work

Institute of Systemic Inflammation Research

230 Citations (Scopus)

Abstract

Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human Tcells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. Tcells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4⁺ Tcell effector function.

Original language	English
Journal	Immunity
Volume	42
Issue number	6
Pages (from-to)	1033-1047
Number of pages	15
ISSN	1074-7613
DOIs	https://doi.org/10.1016/j.immuni.2015.05.024
Publication status	Published - 16.06.2015

Funding

We thank the donors and the patients for their support, Margaret So (University of Arizona) for the anti-CD46 CYT-1 and CYT-2 antibodies and Erez Dror (University of Basel) for help with nutrient uptake studies. This work was supported by the MRC grants G1002165 (C.K.) and MR/J006742/1, an EU-funded Innovative Medicines Initiative BTCURE (C.K.), a Wellcome Trust Investigator Award (C.K), a Wellcome Trust Intermediate Research Fellowship (B.A.), the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust, and King’s College London. S.D. was supported by the Roche Postdoctoral Fellowship Program, C.H. by the Gebert Rüf Foundation (GRS–058/14), and both C.H. and M.F. by the Swiss National Science Foundation (310030-153059 and 323530-139181, respectively). We thank T. Krebs and E. Traunecker for technical assistance with cell sorting.

UN SDGs

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

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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Kolev, M., Dimeloe, S., Le Friec, G., Navarini, A., Arbore, G., Povoleri, G. A., Fischer, M., Belle, R., Loeliger, J., Develioglu, L., Bantug, G. R., Watson, J., Couzi, L., Afzali, B., Lavender, P., Hess, C., & Kemper, C. (2015). Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses. Immunity, 42(6), 1033-1047. https://doi.org/10.1016/j.immuni.2015.05.024

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title = "Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses",

abstract = "Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human Tcells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. Tcells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4+ Tcell effector function.",

author = "Martin Kolev and Sarah Dimeloe and \{Le Friec\}, Gaelle and Alexander Navarini and Giuseppina Arbore and Povoleri, \{Giovanni A.\} and Marco Fischer and R{\'e}ka Belle and Jordan Loeliger and Leyla Develioglu and Bantug, \{Glenn R.\} and Julie Watson and Lionel Couzi and Behdad Afzali and Paul Lavender and Christoph Hess and Claudia Kemper",

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Kolev, M, Dimeloe, S, Le Friec, G, Navarini, A, Arbore, G, Povoleri, GA, Fischer, M, Belle, R, Loeliger, J, Develioglu, L, Bantug, GR, Watson, J, Couzi, L, Afzali, B, Lavender, P, Hess, C & Kemper, C 2015, 'Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses', Immunity, vol. 42, no. 6, pp. 1033-1047. https://doi.org/10.1016/j.immuni.2015.05.024

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T1 - Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

AU - Kolev, Martin

AU - Dimeloe, Sarah

AU - Le Friec, Gaelle

AU - Navarini, Alexander

AU - Arbore, Giuseppina

AU - Povoleri, Giovanni A.

AU - Fischer, Marco

AU - Belle, Réka

AU - Loeliger, Jordan

AU - Develioglu, Leyla

AU - Bantug, Glenn R.

AU - Watson, Julie

AU - Couzi, Lionel

AU - Afzali, Behdad

AU - Lavender, Paul

AU - Hess, Christoph

AU - Kemper, Claudia

PY - 2015/6/16

Y1 - 2015/6/16

N2 - Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human Tcells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. Tcells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4+ Tcell effector function.

AB - Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human Tcells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. Tcells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4+ Tcell effector function.

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SN - 1074-7613

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JO - Immunity

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ER -

Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

Abstract

Funding

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Research Areas and Centers

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