Cytokine-induced human IFN-gamma-secreting effector-memory Th cells in chronic autoimmune inflammation

Blood. 2009 Feb 26;113(9):1948-56. doi: 10.1182/blood-2008-02-139147. Epub 2008 Dec 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / pathology
  • Chronic Disease
  • Cytokines / pharmacology*
  • Female
  • Humans
  • Immunologic Memory / immunology
  • Immunologic Memory / physiology
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interferon-gamma / metabolism*
  • Interleukin-12 / pharmacology
  • Interleukin-18 / pharmacology
  • Male
  • Middle Aged
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • T-Lymphocytes, Helper-Inducer / pathology
  • Young Adult


  • Cytokines
  • Interleukin-18
  • Interleukin-12
  • Interferon-gamma