T cells lacking the IL-27 receptor generate less severe colitis in mice, and more readily up-regulate Foxp3 expression

Ahern

Anderson

Artis

Awasthi

Batten

Chen

Collison

Crabé

Fitzgerald

Honda

Huber

Imielinski

Izcue

Jankovic

Jennifer H. Cox

Kastelein

Lauri Diehl

Leppkes

Marcel Batten

Nandhini Ramamoorthi

Neufert

Nico Ghilardi

Nieuwenhuis

Noelyn M. Kljavin

Omata

O’Connor

Pflanz

Powrie

Schmidt

Shimizu

Stumhofer

Trinchieri

Troy

Uhlig

Villarino

Wang

Yang

Zenewicz

Zheng

English

PubMed

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 (Treg) 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.</jats:p

Crossref

The Journal of Experimental Medicine

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3023127

IL-27 promotes T cell–dependent colitis through multiple mechanisms

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