Hypoxia-inducible factors in CD4 + T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity

Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):8975-8984. doi: 10.1073/pnas.1811702116. Epub 2019 Apr 15.

Abstract

T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4+ and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1α or of both HIF-1α and HIF-2α in CD4+ T cells compromised essential functions in help during antibody responses. HIF-1α depletion from CD4+ T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab after immunization with sheep red blood cells. Compound deficiency of HIF-1α and HIF-2α led to humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4+ cells in the CXCR5+ follicular regulatory population. Glycolysis increases T helper cytokine expression, and HIF promoted glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, IFN-γ elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of help during humoral responses.

Keywords: HIF; T helper cell; humoral immunigy; hypoxia; metabolism.

Publication types

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

MeSH terms

  • Animals
  • Antibody Formation
  • B-Lymphocytes / immunology
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Hypoxia / immunology
  • Cell Hypoxia / physiology
  • Cytokines / metabolism
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Humans
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunity, Humoral
  • Immunization
  • Lymphocyte Activation / immunology
  • Lymphocyte Activation / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, CXCR5 / metabolism
  • Sheep
  • T-Lymphocytes, Helper-Inducer / immunology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cytokines
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, CXCR5
  • endothelial PAS domain-containing protein 1