Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

被引：211

作者：

Kolev, Martin ^{[1
]}

Dimeloe, Sarah ^{[2
]}

Le Friec, Gaelle ^{[1
]}

Navarini, Alexander ^{[3
]}

Arbore, Giuseppina ^{[1
]}

Povoleri, Giovanni A. ^{[1
,4
]}

Fischer, Marco ^{[2
]}

Belle, Reka ^{[2
]}

Loeliger, Jordan ^{[2
]}

Develioglu, Leyla ^{[2
]}

Bantug, Glenn R. ^{[2
]}

Watson, Julie ^{[5
]}

Couzi, Lionel ^{[6
]}

Afzali, Behdad ^{[1
,4
,7
]}

Lavender, Paul ^{[5
]}

Hess, Christoph ^{[2
]}

Kemper, Claudia ^{[1
]}

机构：

[1] Guys Hosp, Kings Coll London, MRC Ctr Transplantat, Div Transplant Immunol & Mucosal Biol, London SE1 9RT, England

[2] Univ Basel, Dept Biomed Immunobiol, CH-4031 Basel, Switzerland

[3] Univ Zurich Hosp, Dept Dermatol, Zurich, Switzerland

[4] Guys Hosp, Biomed Res Ctr, Kings Hlth Partners, London SE1 9RT, England

[5] Guys Hosp, Kings Coll London, MRC & Asthma UK Ctr Allerg Mech Asthma, London SE1 9RT, England

[6] Hosp Pellegrin, CNRS, CHU Bordeaux, Nephrol Transplantat,UMR 1564, F-33076 Bordeaux, France

[7] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA

来源：

IMMUNITY | 2015年 / 42卷 / 06期

基金：

英国惠康基金; 瑞士国家科学基金会;

关键词：

HEMOLYTIC-UREMIC SYNDROME; COFACTOR PROTEIN CD46; T-CELLS; EFFECTOR FUNCTION; MAMMALIAN TARGET; GLUCOSE-UPTAKE; GLYCOLYTIC SWITCH; AMINO-ACIDS; ACTIVATION; EXPRESSION;

D O I：

10.1016/j.immuni.2015.05.024

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 T cells, 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. T cells 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-gamma 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(+) T cell effector function.

引用

页码：1033 / 1047

页数：15

共 56 条

[1] CD46, a new costimulatory molecule for T cells, that induces p120CBL and LAT phosphorylation [J].