Cutting Edge: The Silent Chemokine Receptor D6 Is Required for Generating T Cell Responses That Mediate Experimental Autoimmune Encephalomyelitis

Abstract

D6, a promiscuous nonsignaling chemokine binding molecule expressed on the lymphatic endothelium, internalizes and degrades CC chemokines, and D6−/− mice demonstrated increased cutaneous inflammation following topical phorbol ester or CFA injection. We report that D6−/− mice were unexpectedly resistant to the induction of experimental autoimmune encephalomyelitis due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35–55 in CFA, D6−/− mice showed reduced spinal cord inflammation and demyelination with lower incidence and severity of experimental autoimmune encephalomyelitis attacks as compared with D6+/+ littermates. In adoptive transfer studies, MOG-primed D6+/− T cells equally mediated disease in D6+/+ or D6−/− mice, whereas cells from D6−/− mice transferred disease poorly to D6+/− recipients. Lymph node cells from MOG-primed D6−/− mice showed weak proliferative responses and made reduced IFN-γ but normal IL-5. CD11c+ dendritic cells accumulated abnormally in cutaneous immunization sites of D6−/− mice. Surprisingly, D6, a “silent” chemokine receptor, supports immune response generation.

D6 and the atypical chemokine receptor family: Novel regulators of immune and inflammatory processes

“…Similar results have also been reported from a study involving injection of the 'mog' antigen into subcutaneous sites in D6-null mice [65] (see section Central nervous system inflammatory/immune models for more details of this study).…”

“…Thus, D6-null mice display a significantly lesser response in the EAE model characterised by reduced inflammatory leukocyte accumulation in the spinal chord and an attendant reduction in demyelination [65]. This outcome is associated with a significantly attenuated immune response in the D6-null mice to the EAE-inducing 'mog' antigen although the reasons behind this are not yet apparent.…”

Hemopoietic Cell Expression of the Chemokine Decoy Receptor D6 Is Dynamic and Regulated by GATA1

“…For example, the high levels of expression on B cells and DCs suggest that D6, in addition to regulating inflammation, may also be involved in aspects of initiation of the adaptive immune response. We have recently published results from a collaborative study indicating that D6-null mice have a lessened response in the experimental autoimmune encephalomyelitis model of multiple sclerosis (21). Although we have argued that there may be explanations for this that are consistent with D6 regulation of inflammatory chemokine levels at inflamed sites (20), it is possible that D6 expression on B cells and DCs is indicating a more direct role for D6, perhaps in the process of Ag presentation.…”

“…We, and others, have previously described D6 immunostaining on LECs (19) and syncytial trophoblasts (15) and had postulated that D6 on these cells is central to its ability to scavenge inflammatory CC chemokines and thus contribute to the resolution of local inflammatory responses. However, there are aspects of lymphatic vascular physiology that do not fit comfortably with this model (20) and do not easily account for possible roles for D6 in the regulation of immune responses (21). Thus, we set out to identify other sources of D6-expressing cells that may be more suited to the scavenging of chemokines at inflamed sites or to the D6-dependent regulation of the immune response.…”

“…For example, lymphatic vessels are separated by relatively large distances (100 -500 m), thus chemokines, within intervening tissue spaces, are unlikely to come in contact with, and be degraded by, D6 on LECs. In addition, recent data on the reduced response of D6-null mice in experimental autoimmune encephalomyelitis models (21) suggests additional roles for D6 in the regulation of the immune response that may not be dependent on LEC-expressed D6. This led us to examine other possible cells for D6 expression in the hope of identifying alternative vehicles for in vivo D6 functions.…”