Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

Immunity. 2015 Jun 16;42(6):1033-47. doi: 10.1016/j.immuni.2015.05.024.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Cellular Reprogramming / immunology
  • Complement System Proteins / immunology*
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Glycolysis
  • Hemolytic-Uremic Syndrome / immunology*
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunity, Cellular / genetics
  • Interferon-gamma / metabolism
  • Large Neutral Amino Acid-Transporter 1 / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Cofactor Protein / genetics
  • Membrane Cofactor Protein / metabolism*
  • Monomeric GTP-Binding Proteins / metabolism
  • Multiprotein Complexes / metabolism
  • Neuropeptides / metabolism
  • Oxidative Phosphorylation
  • RNA, Small Interfering / genetics
  • Ras Homolog Enriched in Brain Protein
  • TOR Serine-Threonine Kinases / metabolism
  • Th1 Cells / physiology*
  • Up-Regulation

Substances

  • Adaptor Proteins, Signal Transducing
  • Glucose Transporter Type 1
  • Homeodomain Proteins
  • LAMTOR5 protein, human
  • Large Neutral Amino Acid-Transporter 1
  • Membrane Cofactor Protein
  • Multiprotein Complexes
  • Neuropeptides
  • RHEB protein, human
  • RNA, Small Interfering
  • Ras Homolog Enriched in Brain Protein
  • RAG-1 protein
  • Interferon-gamma
  • Complement System Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Monomeric GTP-Binding Proteins

Associated data

  • GEO/GSE69090