HIF1α-Dependent Metabolic Signals Control the Differentiation of Follicular Helper T Cells.

Dong Dong,He He,Liu Liu,Cao Cao,Zhou Zhou,Bi Bi,Li Li

doi:10.3390/cells8111450

Dong Dong, He He + Show 5 more

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https://doi.org/10.3390/cells8111450

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Abstract

Follicular helper T (TFH) cells are critical for germinal center (GC) formation and are responsible for effective B cell-mediated immunity; metabolic signaling is an important regulatory mechanism for the differentiation of TFH cells. However, the precise roles of hypoxia inducible factor (HIF) 1α-dependent glycolysis and oxidative phosphorylation (OXPHOS) metabolic signaling remain unclear in TFH cell differentiation. Herein, we investigated the effects of glycolysis and OXPHOS on TFH cell differentiation and GC responses using a pharmacological approach in mice under a steady immune status or an activated immune status, which can be caused by foreign antigen stimulation and viral infection. GC and TFH cell responses are related to signals from glycolytic metabolism in mice of different ages. Foreign, specific antigen-induced GC, and TFH cell responses and metabolic signals are essential upon PR8 infection. Glycolysis and succinate-mediated OXPHOS are required for the GC response and TFH cell differentiation. Furthermore, HIF1α is responsible for glycolysis- and OXPHOS-induced alterations in the GC response and TFH cell differentiation under steady or activated conditions in vivo. Blocking glycolysis and upregulating OXPHOS signaling significantly recovered TFH cell differentiation upon PR8 infection and ameliorated inflammatory damage in mice. Thus, our data provide a comprehensive experimental basis for fully understanding the precise roles of HIF1α-mediated glycolysis and OXPHOS metabolic signaling in regulating the GC response and TFH cell differentiation during stable physiological conditions or an antiviral immune response.

Highlights

Follicular helper T (TFH ) cells are specialized T helper (TH ) cells that localize in the follicles and germinal center (GC) and can selectively stimulate B cells for GC responses, contributing to immunoglobulin production and memory B cell and long-lived plasma cell development [1,2]
IL-21 is critical for TFH cell differentiation and function, and we found that IL-21 production in TFH cells showed a consistent tendency with age (Figure 1B)
The results showed that OVA immunization markedly enhanced TFH cell differentiation and GC responses, but Suc combined with OVA immunization treatment significantly recovered these alterations (Figure 5A,B)

Summary

Introduction

Follicular helper T (TFH ) cells are specialized T helper (TH ) cells that localize in the follicles and germinal center (GC) and can selectively stimulate B cells for GC responses, contributing to immunoglobulin production and memory B cell and long-lived plasma cell development [1,2]. Bcl-6 is a master-specific transcriptional factor for TFH cells [10,11,12]. ICOS and its ligand are required for Bcl-6 expression and TFH cell differentiation [13,14,15]. IL-2 potently inhibited TFH cell differentiation through the transcription factors STAT5 and Blimp, which can significantly inhibit the expression of Bcl-6 [16,17,18]

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