Functional Analysis of Immune Signature Genes in Th1* Memory Cells Links ISOC1 and Pyrimidine Metabolism to IFN-γ and IL-17 Production

J Immunol. 2021 Mar 15;206(6):1181-1193. doi: 10.4049/jimmunol.2000672. Epub 2021 Feb 5.

Abstract

CCR6+CXCR3+CCR4-CD4+ memory T cells, termed Th1*, are important for long-term immunity to Mycobacterium tuberculosis and the pathogenesis of autoimmune diseases. Th1* cells express a unique set of lineage-specific transcription factors characteristic of both Th1 and Th17 cells and display distinct gene expression profiles compared with other CD4+ T cell subsets. To examine molecules and signaling pathways important for the effector function of Th1* cells, we performed loss-of-function screening of genes selectively enriched in the Th1* subset. The genetic screen yielded candidates whose depletion significantly impaired TCR-induced IFN-γ production. These included genes previously linked to IFN-γ or M. tuberculosis susceptibility and novel candidates, such as ISOC1, encoding a metabolic enzyme of unknown function in mammalian cells. ISOC1-depleted T cells, which produced less IFN-γ and IL-17, displayed defects in oxidative phosphorylation and glycolysis and impairment of pyrimidine metabolic pathway. Supplementation with extracellular pyrimidines rescued both bioenergetics and IFN-γ production in ISOC1-deficient T cells, indicating that pyrimidine metabolism is a key driver of effector functions in CD4+ T cells and Th1* cells. Results provide new insights into the immune-stimulatory function of ISOC1 as well as the particular metabolic requirements of human memory T cells, providing a novel resource for understanding long-term T cell-driven responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation / immunology
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Healthy Volunteers
  • Humans
  • Hydrolases / genetics
  • Hydrolases / metabolism*
  • Immunologic Memory / genetics
  • Interferon-gamma / genetics*
  • Interleukin-17 / genetics*
  • Primary Cell Culture
  • Pyrimidines / metabolism
  • RNA, Small Interfering / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism

Substances

  • IFNG protein, human
  • Interleukin-17
  • Pyrimidines
  • RNA, Small Interfering
  • Interferon-gamma
  • Hydrolases
  • ISOC1 protein, human