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Cell Rep. 2019 Aug 13;28(7):1758-1772.e4. doi: 10.1016/j.celrep.2019.07.034.
Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection.
Sheikh AA1, Cooper L2, Feng M1, Souza-Fonseca-Guimaraes F1, Lafouresse F3, Duckworth BC1, Huntington ND4, Moon JJ5, Pellegrini M6, Nutt SL1, Belz GT1, Good-Jacobson KL2, Groom JR7.
Author information
1 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. 2 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. 3 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Centre de Recherches en Canc?rologie de Toulouse, INSERM U1037, Equipe labellis?e Ligue Nationale contre le cancer, Universit? de Toulouse III-Paul Sabatier, Toulouse, France. 4 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. 5 Center for Immunology and Inflammatory Diseases, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, and Harvard Medical School, Charlestown, MA 02129, USA. 6 Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Division of Infection and Immunity, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. 7 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: groom@wehi.edu.au.
Abstract
Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination.
Copyright ? 2019 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
T cell differentiation; T follicular helper; T helper 1; T-bet; germinal center; influenza; isotope switching; transcriptional regulation; viral infection
PMID: 31412245 DOI: 10.1016/j.celrep.2019.07.034
Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection.
Sheikh AA1, Cooper L2, Feng M1, Souza-Fonseca-Guimaraes F1, Lafouresse F3, Duckworth BC1, Huntington ND4, Moon JJ5, Pellegrini M6, Nutt SL1, Belz GT1, Good-Jacobson KL2, Groom JR7.
Author information
1 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. 2 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. 3 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Centre de Recherches en Canc?rologie de Toulouse, INSERM U1037, Equipe labellis?e Ligue Nationale contre le cancer, Universit? de Toulouse III-Paul Sabatier, Toulouse, France. 4 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. 5 Center for Immunology and Inflammatory Diseases, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, and Harvard Medical School, Charlestown, MA 02129, USA. 6 Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Division of Infection and Immunity, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. 7 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: groom@wehi.edu.au.
Abstract
Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination.
Copyright ? 2019 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
T cell differentiation; T follicular helper; T helper 1; T-bet; germinal center; influenza; isotope switching; transcriptional regulation; viral infection
PMID: 31412245 DOI: 10.1016/j.celrep.2019.07.034