title: Cytokine-dependent induction of CD4+ T cells with cytotoxic potential during influenza virus infection.
abstract: Recent evidence has identified the role of granzyme B- and perforin-expressing CD4(+) T cells with cytotoxic potential in antiviral immunity. However, the in vivo cytokine cues and downstream pathways governing the differentiation of these cells are unclear. Here, we have identified that CD4(+) T cells with cytotoxic potential are specifically induced at the site of infection during influenza virus infection. The development of CD4(+) T cells with cytotoxic potential in vivo was dependent on the cooperation of the STAT2-dependent type I interferon signaling and the interleukin-2/interleukin-2 receptor alpha pathway for the induction of the transcription factors T-bet and Blimp-1. We showed that Blimp-1 promoted the binding of T-bet to the promoters of cytolytic genes in CD4(+) T cells and was required for the cytolytic function of the in vitro- and in vivo-generated CD4(+) T cells with cytotoxic potential. Thus, our data define the molecular basis of regulation of the in vivo development of this functionally cytotoxic Th subset during acute respiratory virus infection. The potential implications for the functions of these cells are discussed.
authors.affiliation: Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Laiqing
authors.initials: L
authors.lastname: Hua
authors.forename: Shuyu
authors.initials: S
authors.lastname: Yao
authors.forename: Duy
authors.initials: D
authors.lastname: Pham
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wright
authors.forename: Deepali
authors.initials: D
authors.lastname: Sawant
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Dent
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Braciale
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D016207:Cytokines