title: Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells.
abstract: Human memory T cells (T(M) cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively. These T cell lineages are almost exclusively CCR6(+) and are important mediators of chronic inflammation and autoimmunity. However, little is known about the mechanisms controlling IL-17/IL-22 expression in memory Th17/Th22 subsets. We show that common γ chain (γc)-using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17-signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6(+), but not CCR6(-), T(M) cells, even in CCR6(+) cells lacking IL-17 expression ex vivo. Inhibition of phosphoinositide 3-kinase (PI-3K) or Akt signaling selectively prevents Th17 cytokine induction by γc-cytokines, as does ectopic expression of the transcription factors FOXO1 or KLF2, which are repressed by PI-3K signaling. These results indicate that Th17 cytokines are tuned by PI-3K signaling in CCR6(+) T(M) cells, which may contribute to chronic or autoimmune inflammation. Furthermore, these findings suggest that ex vivo analysis of IL-17 expression may greatly underestimate the frequency and pathogenic potential of the human Th17 compartment.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
authors.forename: Lina
authors.initials: L
authors.lastname: Kozhaya
authors.forename: Aimee
authors.initials: A
authors.lastname: ElHed
authors.forename: Radha
authors.initials: R
authors.lastname: Ramesh
authors.forename: Thaddeus J
authors.initials: TJ
authors.lastname: Carlson
authors.forename: Ivana M
authors.initials: IM
authors.lastname: Djuretic
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sundrud
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D054399:Receptors, CCR6; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: C106311:CCR6 protein, human; C498126:CCR6 protein, mouse; D016207:Cytokines; D054399:Receptors, CCR6; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt