TY - JOUR
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
N1 - Publisher Copyright:
© 2015 The Authors.
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.
UR - http://www.scopus.com/inward/record.url?scp=84937604783&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2015.05.024
DO - 10.1016/j.immuni.2015.05.024
M3 - Journal articles
C2 - 26084023
AN - SCOPUS:84937604783
SN - 1074-7613
VL - 42
SP - 1033
EP - 1047
JO - Immunity
JF - Immunity
IS - 6
ER -
