title: The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa.
abstract: T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-βR signaling, suggesting that TGF-β insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, United States.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Marshall
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Ray
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Laidlaw
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, United States.
authors.forename: Nianzhi
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, United States.
authors.forename: Dipika
authors.initials: D
authors.lastname: Gawande
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, United States.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Staron
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, United States.
authors.forename: Joe
authors.initials: J
authors.lastname: Craft
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D009092:Mucous Membrane / Q000276:immunology* / Q000473:pathology / Q000821:virology; D009975:Orthomyxoviridae / Q000502:physiology; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D013045:Species Specificity; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D058570:TOR Serine-Threonine Kinases
keywords: T follicular helper cells; TGF-beta; antibody; cytokines; immunology; mouse; viral infection