IL-27 promotes T cell?dependent colitis through multiple mechanisms
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-gamma and IL-10 and lacking forkhead box P3 (Foxp3). Accordingly, IL-27 receptor alpha (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-gamma 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.
|ISBN||1540-9538 (Electronic) 0022-1007 (Linking)|
|Authors||Cox, J. H.; Kljavin, N. M.; Ramamoorthi, N.; Diehl, L.; Batten, M.; Ghilardi, N.|
|Publisher Name||JOURNAL OF EXPERIMENTAL MEDICINE|
|DOI||jem.20100410 [pii] 10.1084/jem.20100410|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21173106|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10918|