title: Cytokine-induced human IFN-gamma-secreting effector-memory Th cells in chronic autoimmune inflammation.
abstract: T-helper (Th) cells activated by cytokines in the absence of T-cell receptor ligation are suspected to participate in inflammatory processes by production of interferon-gamma (IFN-gamma). Still, the relevance of such a mechanism has not been addressed in humans. Here we demonstrate that a subset of human effector-memory Th cells expressing functional interleukin-12R (IL-12R), IL-18Ralpha, and CCR5 ex vivo can be induced to secrete IFN-gamma by cytokines signaling via the IL-2R common gamma-chain in combination with IL-12 and IL-18. Cytokine-driven IFN-gamma production depends on JAK3- and p38 mitogen-activated kinase signals and is sensitive to suppression by CD25(++) regulatory T cells. Contrary to IFN-gamma(+) Th cells induced upon antigen-specific stimulation, their cytokine-activated counterparts characteristically lack expression of costimulator 4-1BB (CD137). Strikingly, the majority of Th cells infiltrating inflamed joints of rheumatoid arthritis patients is equipped with receptors prerequisite for cytokine-induced IFN-gamma secretion. Among these cells, we detected a substantial fraction that secretes IFN-gamma directly ex vivo but lacks 4-1BB expression, indicating that cytokine-induced IFN-gamma(+) Th cells operate in autoimmune inflammation. Our data provide a rationale for how human effector-memory Thcells can participate in perpetuating inflammatory processes in autoimmunity even in the absence of T-cell receptor ligation.
authors.affiliation: Clinical Immunology Group, German Rheumatism Research Centre, Berlin, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Sattler
authors.forename: Ulf
authors.initials: U
authors.lastname: Wagner
authors.forename: Manuela
authors.initials: M
authors.lastname: Rossol
authors.forename: Joachim
authors.initials: J
authors.lastname: Sieper
authors.forename: Peihua
authors.initials: P
authors.lastname: Wu
authors.forename: Andreas
authors.initials: A
authors.lastname: Krause
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Schmidt
authors.forename: Sebastian
authors.initials: S
authors.lastname: Radmer
authors.forename: Siegfried
authors.initials: S
authors.lastname: Kohler
authors.forename: Chiara
authors.initials: C
authors.lastname: Romagnani
authors.forename: Andreas
authors.initials: A
authors.lastname: Thiel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology / Q000502:physiology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D016207:Cytokines; D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma