title: IL-27 promotes T cell-dependent colitis through multiple mechanisms.
abstract: Interleukin-27 (IL-27) is a cytokine known to have both proinflammatory and immunoregulatory functions. The latter appear to dominate in vivo, where IL-27 suppresses TH17 responses and promotes the differentiation of Tr1 cells expressing interferon-γ and IL-10 and lacking forkhead box P3 (Foxp3). Accordingly, IL-27 receptor α (Il27ra)-deficient mice suffer from exacerbated immune pathology when infected with various parasites or challenged with autoantigens. Because the role of IL-27 in human and experimental mouse colitis is controversial, we studied the consequences of Il27ra deletion in the mouse T cell transfer model of colitis and unexpectedly discovered a proinflammatory role of IL-27. Absence of Il27ra on transferred T cells resulted in diminished weight loss and reduced colonic inflammation. A greater fraction of transferred T cells assumed a Foxp3(+) phenotype in the absence of Il27ra, suggesting that IL-27 functions to restrain regulatory T cell (T(reg)) development. Indeed, IL-27 suppressed Foxp3 induction in vitro and in an ovalbumin-dependent tolerization model in vivo. Furthermore, effector cell proliferation and IFN-γ production were reduced in the absence of Il27ra. Collectively, we describe a proinflammatory role of IL-27 in T cell-dependent intestinal inflammation and provide a rationale for targeting this cytokine in pathological situations that result from a breakdown in peripheral immune tolerance.
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Cox
authors.forename: Noelyn M
authors.initials: NM
authors.lastname: Kljavin
authors.forename: Nandhini
authors.initials: N
authors.lastname: Ramamoorthi
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.forename: Marcel
authors.initials: M
authors.lastname: Batten
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
mesh_terms: D000818:Animals; D016764:Cell Polarity; D003092:Colitis / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000172:deficiency / Q000378:metabolism; D018123:Receptors, Interleukin; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: C484747:Il27ra protein, mouse; D020381:Interleukin-17; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin