4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Follicular helper T (T FH) 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 T FH cells. However, the precise roles of hypoxia inducible factor (HIF) 1α-dependent glycolysis and oxidative phosphorylation (OXPHOS) metabolic signaling remain unclear in T FH cell differentiation. Herein, we investigated the effects of glycolysis and OXPHOS on T FH 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 T FH cell responses are related to signals from glycolytic metabolism in mice of different ages. Foreign, specific antigen-induced GC, and T FH cell responses and metabolic signals are essential upon PR8 infection. Glycolysis and succinate-mediated OXPHOS are required for the GC response and T FH cell differentiation. Furthermore, HIF1α is responsible for glycolysis- and OXPHOS-induced alterations in the GC response and T FH cell differentiation under steady or activated conditions in vivo. Blocking glycolysis and upregulating OXPHOS signaling significantly recovered T FH 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 T FH cell differentiation during stable physiological conditions or an antiviral immune response.

          Related collections

          Most cited references34

          • Record: found
          • Abstract: found
          • Article: not found

          Cellular metabolism and macrophage functional polarization.

          Macrophages are a functionally heterogeneous cell population that is mainly shaped by a variety of microenvironmental stimuli. Interferon γ (IFN-γ), interleukin-1β (IL-1β), and lipopolysaccharide (LPS) induce a classical activation of macrophages (M1), whereas IL-4 and IL-13 induce an alternative activation program in macrophages (M2). Reprogramming of intracellular metabolisms is required for the proper polarization and functions of activated macrophages. Similar to the Warburg effect observed in tumor cells, M1 macrophages increase glucose consumption and lactate release and decreased oxygen consumption rate. In comparison, M2 macrophages mainly employ oxidative glucose metabolism pathways. In addition, fatty acids, vitamins, and iron metabolisms are also related to macrophage polarization. However, detailed metabolic pathways involved in macrophages have remained elusive. Understanding the bidirectional interactions between cellular metabolism and macrophage functions in physiological and pathological situations and the regulatory pathways involved may offer novel therapies for macrophage-associated diseases.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Regulation of the Germinal Center Response

            The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity. However, this mutation process can also be dangerous, as it can create autoreactive clones that can cause autoimmunity. Because of this, regulation of GC reactions is critical to ensure high affinity antibody production and to enforce self-tolerance by avoiding emergence of autoreactive B cell clones. A productive GC response requires the collaboration of multiple cell types. The stromal cell network orchestrates GC cell dynamics by controlling antigen delivery and cell trafficking. T follicular helper (Tfh) cells provide specialized help to GC B cells through cognate T-B cell interactions while Foxp3+ T follicular regulatory (Tfr) cells are key mediators of GC regulation. However, regulation of GC responses is not a simple outcome of Tfh/Tfr balance, but also involves the contribution of other cell types to modulate the GC microenvironment and to avoid autoimmunity. Thus, the regulation of the GC is complex, and occurs at multiple levels. In this review we outline recent developments in the biology of cell subsets involved in the regulation of GC reactions, in both secondary lymphoid tissues, and Peyer's patches (PPs). We discuss the mechanisms which enable the generation of potent protective humoral immunity whilst GC-derived autoimmunity is avoided.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells.

              Blimp1, a transcriptional repressor, has a crucial role in the specification of primordial germ cells (PGCs) in mice at embryonic day 7.5 (E7.5). This SET-PR domain protein can form complexes with various chromatin modifiers in a context-dependent manner. Here, we show that Blimp1 has a novel interaction with Prmt5, an arginine-specific histone methyltransferase, which mediates symmetrical dimethylation of arginine 3 on histone H2A and/or H4 tails (H2A/H4R3me2s). Prmt5 has been shown to associate with Tudor, a component of germ plasm in Drosophila melanogaster. Blimp1-Prmt5 colocalization results in high levels of H2A/H4 R3 methylation in PGCs at E8.5. However, at E11.5, Blimp1-Prmt5 translocates from the nucleus to the cytoplasm, resulting in the loss of H2A/H4 R3 methylation at the time of extensive epigenetic reprogramming of germ cells. Subsequently, Dhx38, a putative target of the Blimp1-Prmt5 complex, is upregulated. Interestingly, expression of Dhx38 is also seen in pluripotent embryonic germ cells that are derived from PGCs when Blimp1 expression is lost. Our study demonstrates that Blimp1 is involved in a novel transcriptional regulatory complex in the mouse germ-cell lineage.
                Bookmark

                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                17 November 2019
                November 2019
                : 8
                : 11
                : 1450
                Affiliations
                [1 ]Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; 201731200020@ 123456mail.bnu.edu.cn (L.D.); 201821200008@ 123456mail.bnu.edu.cn (Y.H.); 201921200005@ 123456mail.bnu.edu.cn (Y.C.); liyan1106369@ 123456163.com (Y.L.)
                [2 ]Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan 250062, China; shupzhou718@ 123456163.com
                [3 ]State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
                Author notes
                [* ]Correspondence: byj7801@ 123456sina.com (Y.B.); liugw@ 123456bnu.edu.cn (G.L.); Tel./Fax: +86-10-66948562 (Y.B.); +86-10-58800026 (G.L.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-6008-2891
                Article
                cells-08-01450
                10.3390/cells8111450
                6912655
                31744227
                c34ec337-99b4-41b4-9e1c-e4fd017a56a6
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 October 2019
                : 15 November 2019
                Categories
                Article

                follicular helper t cell,t cell differentiation,hif1α,glycolysis,oxidative phosphorylation,virus infection,infectious inflammation,gc responses,b cell immunity

                Comments

                Comment on this article