期刊
IMMUNITY
卷 42, 期 6, 页码 1033-1047出版社
CELL PRESS
DOI: 10.1016/j.immuni.2015.05.024
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资金
- MRC [G1002165, MR/J006742/1]
- EU
- Wellcome Trust
- National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust, and King's College London
- Roche
- Gebert Ruf Foundation [GRS-058/14]
- Swiss National Science Foundation [310030-153059, 323530-139181]
- MRC [G1002165] Funding Source: UKRI
- Swiss National Science Foundation (SNF) [323530-139181, 310030_153059] Funding Source: Swiss National Science Foundation (SNF)
- Medical Research Council [G1000758, MR/J006742/1, G1002165] Funding Source: researchfish
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.
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