Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection
Amania A. Sheikh,
Lucy Cooper,
Meiqi Feng,
Fernando Souza-Fonseca-Guimaraes,
Fanny Lafouresse,
Brigette C. Duckworth,
Nicholas D. Huntington,
James J. Moon,
Marc Pellegrini,
Stephen L. Nutt,
Gabrielle T. Belz,
Kim L. Good-Jacobson,
Joanna R. Groom
Affiliations
Amania A. Sheikh
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
Lucy Cooper
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Meiqi Feng
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
Fernando Souza-Fonseca-Guimaraes
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
Fanny Lafouresse
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
Brigette C. Duckworth
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
Nicholas D. Huntington
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
James J. Moon
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
Marc Pellegrini
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
Stephen L. Nutt
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
Gabrielle T. Belz
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
Kim L. Good-Jacobson
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Joanna R. Groom
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; Corresponding author
Summary: 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. : Shiekh et al. show that, in influenza and LCMV infections, the role of the transcription factor T-bet in TFH differentiation is contingent on environmental cues, IL-2 signaling, and T cell competition. Cell-specific T-bet expression independently drives antibody isotype class switching. Therefore T-bet instructs immune protection in a context-dependent manner. Keywords: T cell differentiation, T follicular helper, T helper 1, T-bet, germinal center, influenza, viral infection, transcriptional regulation, isotope switching
