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
118 Citations (Scopus)


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 languageEnglish
Issue number6
Pages (from-to)1033-1047
Number of pages15
Publication statusPublished - 16.06.2015

Research Areas and Centers

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


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