title: STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection.
abstract: γδ T cells are prevalent at mucosal and epithelial surfaces and are a critical first line of defense against bacterial and fungal pathogens. γδ17 cells are a subset of γδ T cells which, in the presence of IL-23 and IL-1β, produce large quantities of interleukin-17A (IL-17A), a cytokine crucial to these cells' antibacterial and antifungal function. STAT6, an important transcription factor in Th2 differentiation and inhibition of Th1 differentiation, is expressed at high levels in the T cells of people with parasitic infections and asthma. Our group and others have shown that STAT6 attenuates IL-17A protein expression by CD4(+) T cells. By extension, we hypothesized that STAT6 activation also inhibits innate γδ17 cell cytokine secretion. We show here that γδ17 cells expressed the type I IL-4 receptor (IL-4R), and IL-4 increased STAT6 phosphorylation in γδ T cells. IL-4 inhibited γδ17 cell production of IL-17A. IL-4 also decreased γδ17 cell expression of IL-23R as well as Sgk1. To determine whether STAT6 signaling regulates γδ17 cell numbers in vivo, we used a model of Klebsiella pneumoniae in mice deficient in STAT6. We chose K. pneumoniae for our in vivo model, since K. pneumoniae increases IL-17A expression and γδ17 numbers. K. pneumoniae infection of STAT6 knockout mice resulted in a statistically significant increase in the number of γδ17 cells compared to that of wild-type mice. These studies are the first to demonstrate that γδ17 cells express the type I IL-4R and that STAT6 signaling negatively regulates γδ17 cells, a cell population that plays a front-line role in mucosal immunity.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Bloodworth
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Dulek
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Stier
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jacqueline Y
authors.initials: JY
authors.lastname: Cephus
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewska
authors.affiliation: Department of Pediatrics, University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA stokes.peebles@vanderbilt.edu.|Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018928:Immunity, Mucosal; D020381:Interleukin-17 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D007710:Klebsiella Infections / Q000473:pathology*; D007711:Klebsiella pneumoniae / Q000276:immunology*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D020381:Interleukin-17; D015847:Interleukin-4; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C494100:Stat6 protein, mouse