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

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

Author information

1
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; sunghoon.cho@vanderbilt.edu mark.boothby@vanderbilt.edu.
2
Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232.
3
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.
4
Department of Physiology, McGill University, Montreal, QC, Canada H3A 0G4.
5
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
6
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232.
7
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232.
8
Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212.
9
Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37212.

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

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