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

Cho SH, Raybuck AL, Blagih J, Kemboi E, Haase VH, Jones RG, Boothby MR
Proc Natl Acad Sci U S A. 2019 116 (18): 8975-8984

PMID: 30988188 · PMCID: PMC6500120 · DOI:10.1073/pnas.1811702116

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.

MeSH Terms (20)

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

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