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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-04, Vol.116 (18), p.8975-8984
• Main Authors: Cho, Sung Hoon, Raybuck, Ariel L., Blagih, Julianna, Kemboia, Edna, Haase, Volker H., Jones, Russell G., Boothby, Mark R.
• Format: Article
• Language: English
• Subjects: Animals; Antibody Formation; Antigens; B-Lymphocytes - immunology; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD40 antigen; CD40L protein; Cell activation; Cell Hypoxia - immunology; Cell Hypoxia - physiology; Class switching; CXCR5 protein; Cytokines; Cytokines - metabolism; Depletion; Erythrocytes; Foxp3 protein; Germinal Center - immunology; Germinal Center - metabolism; Glycolysis; Helper cells; Humans; Humoral immunity; Hypoxia; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Immunity; Immunity, Humoral; Immunization; Immunoglobulins; Lymphocyte Activation - immunology; Lymphocyte Activation - physiology; Lymphocytes; Lymphocytes B; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular modelling; PNAS Plus; Receptors, CXCR5 - metabolism; Sheep; Sheep red blood cells; Switching; T cell receptors; T-Lymphocytes, Helper-Inducer - immunology; Transcription factors; γ-Interferon
• ISSN: 0027-8424; 1091-6490
• 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.