TY - JOUR
T1 - Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses
AU - Kolev, M
AU - Dimeloe, Sarah
AU - Le Friec, G
AU - Navarini, A
AU - Arbore, G
AU - Povoleri, G
AU - Fischer, M
AU - Belle, Reka
AU - Loeliger, J
AU - Develioglu, Leyla
AU - Bantug, Glenn
AU - Watson, J
AU - Couzi, Lionel
AU - Afzali, Behdad
AU - Lavender, Paul
AU - Hess, Christoph
AU - Kemper, C
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 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-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(+) T cell 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 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-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(+) T cell effector function.
U2 - 10.1016/j.immuni.2015.05.024
DO - 10.1016/j.immuni.2015.05.024
M3 - Article
SN - 1074-7613
VL - 42
SP - 1033
EP - 1047
JO - Immunity
JF - Immunity
IS - 6
ER -