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

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.

Protection of bona fide T follicular memory cells during tissue isolation reveals their persistence, plasticity and functional impact

“…The top defining genes in the TFH clusters included established TFH markers such as Izumo1r (encoding FR4), Pdcd1, Sh2d1a, as well as transcription factors known to be expressed by CD4 memory cells, including cells Klf6,Jun and Junb (Figures 2B and 2C) (Crawford 9 expressed a partially overlapping transcriptional signature with tissue resident memory cells, highlighting the non-circulating status of this population ( Figure S2G). Notably, Hif1a, a transcription factor normally associated with glycolysis, was one of the top genes expressed by TFH memory cells, consistent with the recently reported high expression of this transcription factor in TFH effectors and resident memory cells ( Figure 2B) (Cho et al, 2019;Hombrink et al, 2016;Zhu et al, 2019).…”

Hypoxia-Driven Immune Escape in the Tumor Microenvironment

“…Well established as a mainstay of GC architecture, hypoxia drives response mechanisms and T cell function in response to the generation of antibodies. In particular, depletion of HIF-1α from CD4 + T cells has been shown to reduce frequencies of antigen-specific GC B cells, follicular T helper (Tfh) cells and antigen-specific antibodies [41].…”

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

“…In addition to CXCR5, CCR7, PSGL1, and S1P receptors that are involved in cell migration, SLAM family receptors and integrins are also involved in regulating Tfh cell functions [32]. In addition, other regulators, including ICOSL [222], Ascl2 [229], Itch [230], VHL [231], IL-37 [232], HIF-1α [233], COX-1 [234], Th-POK [235], and Tox2 [236] are also found to be important for Tfh cell differentiation and functions. Tfh cells provide help to GC B cells in two aspects: one is to promote GC B cell maturation, and the other is to promote antibody production.…”