title: Altered T-bet dominance in IFN-γ-decoupled CD4+ T cells with attenuated cytokine storm and preserved memory in influenza.
abstract: Cytokine storm has been postulated as one of the major causes of mortality in patients with severe respiratory viral infections such as influenza. With the help of an influenza Ag- specific mouse experimental system, we report that CD4(+) T cells contribute effector cytokines leading to lung inflammation in acute influenza. Although virus can no longer be detected from tissues 14 d postinfection, virus-derived Ag continues to drive a CD4(+) T cell response after viral clearance. Ag-specific CD4(+) T cells proliferate and evolve into memory CD4(+) T cells efficiently, but the production of effector cytokines is seriously hampered during this phase. This decoupling of proliferation and effector cytokine production doesn't appear in conjunction with increased suppression by regulatory T cells or decreased induction of transcription factors. Rather, GATA-3 and ROR-γt levels are elevated when compared with cells that have effector cytokine production. T-bet dominance over GATA-3 and ROR-γt decreases with the disarmament of effector cytokine production. Importantly, upon reinfection, these decoupled cells produce elevated levels of IFN-γ and were effective in virus eradication. These results provide a mechanism through altered T-bet dominance to dampen the cytokine storm without impeding the generation of memory T cells in influenza virus infection.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Chang Gung University and Chang Gung Memorial Hospital, Kweishan, Taoyuan 33333, Taiwan.
authors.forename: Avijit
authors.initials: A
authors.lastname: Dutta
authors.forename: Shi-Chuen
authors.initials: SC
authors.lastname: Miaw
authors.forename: Jhang-Sian
authors.initials: JS
authors.lastname: Yu
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Lin
authors.forename: Yung-Chang
authors.initials: YC
authors.lastname: Lin
authors.forename: Chia-Shiang
authors.initials: CS
authors.lastname: Chang
authors.forename: Yueh-Chia
authors.initials: YC
authors.lastname: He
authors.forename: Sheng-Hao
authors.initials: SH
authors.lastname: Chuang
authors.forename: Ming-I
authors.initials: MI
authors.lastname: Yen
authors.forename: Ching-Tai
authors.initials: CT
authors.lastname: Huang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002642:Chick Embryo; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity; D007371:Interferon-gamma / Q000378:metabolism*; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma