Hypoxia-Inducible Factors (HIF) in CD4+ T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity

Abstract

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 re-stimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide immunoglobulin class switching. Recent work showed that hypoxia is a normal feature of most GC, raising questions about molecular mechanisms governing the relationship between hypoxia and T cell help to antibody response. 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-1a and HIF-2a in CD4+ T cells compromised essential functions in help during antibody responses. HIF-1a depletion from CD4 T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab. Compound deficiency of HIF-1a and HIF-2a intensified humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4+ cells in the CCR5+ follicular regulatory (Tfr) population. Glycolysis increases T helper cytokine expression, and HIF was essential for stimulation of glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, interferon-g 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 follicular help during humoral responses.