title: The atypical chemokine receptor D6 contributes to the development of experimental colitis.
abstract: Proinflammatory CC chemokines control leukocyte recruitment and function during inflammation by engaging chemokine receptors expressed on circulating leukocytes. The D6 chemokine receptor can bind several of these chemokines, but appears unable to couple to signal transduction pathways or direct cell migration. Instead, D6 has been proposed to act as a chemokine scavenger, removing proinflammatory chemokines to dampen leukocyte responses. In this study, we have examined the role of D6 in the colon using the dextran sodium sulfate-induced model of colitis. We show that D6 is expressed in the resting colon, predominantly by stromal cells and B cells, and is up-regulated during colitis. Unexpectedly, D6-deficient mice showed reduced susceptibility to colitis and had less pronounced clinical symptoms associated with this model. D6 deletion had no impact on the level of proinflammatory CC chemokines released from cultured colon explants, or on the balance of leukocyte subsets recruited to the inflamed colon. However, late in colitis, inflamed D6-deficient colons showed enhanced production of several proinflammatory cytokines, including IFN-gamma and IL-17A, and there was a marked increase in IL-17A-secreting gammadelta T cells in the lamina propria. Moreover, Ab-mediated neutralization of IL-17A worsened the clinical symptoms of colitis at these later stages of the response in D6-deficient, but not wild-type, mice. Thus, D6 can contribute to the development of colitis by regulating IL-17A secretion by gammadelta T cells in the inflamed colon.
authors.affiliation: Division of Immunology, Infection, and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Bordon
authors.forename: Chris A H
authors.initials: CA
authors.lastname: Hansell
authors.forename: David P
authors.initials: DP
authors.lastname: Sester
authors.forename: Mairi
authors.initials: M
authors.lastname: Clarke
authors.forename: Allan McI
authors.initials: AM
authors.lastname: Mowat
authors.forename: Robert J B
authors.initials: RJ
authors.lastname: Nibbs