title: IL-18 is required for self-reactive T cell expansion in NOD mice.
abstract: IL-18 has a well-established role in pro-inflammatory responses in the islets in type 1 diabetes. Here, we identify a distinctive role for IL-18 in expanding pathogenic T cells in the periphery of NOD mice. Well in advance of disease onset, the periphery of IL-18-deficient mice exhibits reduced T cell turnover, an increased prevalence of naïve and quiescent T cells, emergence of fewer effector T cells, and disease protection. Islet-reactive T cells fail to become activated in the lymphoid organs of mice lacking IL-18 and their rapid expansion is inhibited. IL-18 secretion by antigen presenting cells increases with advancing disease and is required for expression of its receptor on T cells. Our results demonstrate that induction of the IL-18 receptor reflects a critical stage of autoreactive T cell activation and expansion on the pathway toward effector T cell differentiation. This study therefore assigns a novel role to IL-18 for expanding the pool of islet-destructive T cells during pre-diabetes. This report highlights a new basic mechanism in type 1 diabetes pathogenesis and suggests that targeting the IL-18 pathway should be explored as a potential treatment strategy.
authors.affiliation: University of Nebraska Medical Center, 985965 Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Marleau
authors.forename: Nora E
authors.initials: NE
authors.lastname: Sarvetnick
mesh_terms: D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000032:analysis; D020382:Interleukin-18 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D053724:Receptors, Interleukin-18 / Q000032:analysis; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: C440021:IL17F protein, human; D020381:Interleukin-17; D020382:Interleukin-18; D053724:Receptors, Interleukin-18; D007371:Interferon-gamma