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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.

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 Cancérologie de Toulouse, INSERM U1037, Equipe labellisée Ligue Nationale contre le cancer, Université 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.

KEYWORDS:

T cell differentiation; T follicular helper; T helper 1; T-bet; germinal center; influenza; isotope switching; transcriptional regulation; viral infection

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