Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

TLDR

Th1 cell effector function depends on metabolic reprogramming, yet the signals that drive this adaptation are poorly understood. Autocrine CD46 signaling through its CYT‑1 domain induces amino‑acid and glucose transporters, activates the Ragulator‑Rag‑mTORC1 complex, and enhances glycolysis and oxidative phosphorylation, thereby linking complement to Th1 metabolic reprogramming and cytokine production; CD46 deficiency impairs this program but can be rescued by CYT‑1 expression.

Abstract

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.