CD55 Is Essential for CD103(+) Dendritic Cell Tolerogenic Responses that Protect against Autoimmunity

摘要

Recent studies traced inflammatory bowel disease in some patients to deficiency of CD55 [decay-accelerating factor (DAF)], but the mechanism underlying the linkage remained unclear. Herein, we studied the importance of DAF in enabling processes that program tolerance in the gut and the eye, two immune-privileged sites where immunosuppressive responses are continuously elicited. Unlike oral feeding or ocular injection of ovalbumin in wild-type (WT) mice, which induced dominant immune tolerance, identical treatment of DAF(-/-) mice or DAF(-/-) to WT bone marrow chimeras did not. While 10% to 30% of mesenteric and submandibular lymph node CD4(+) cells became robust T-regulatory cells (Tregs) in WT forkhead box P3 (Foxp3)-green fluorescent protein mice, few in either site became Tregs with little suppressor activity in DAF(-/-) Foxp3-green fluorescent protein mice. Phenotyping of CD103(+) dendritic cells (DCs) from the ovalbumin-fed DAF(-/-) mice showed impaired expression of inducer of costimulation (ICOS) ligand, programmed death receptor 1-ligand 1 (PD1-L1), CxxxC chemokine receptor 1 (Cx3CR1), CCR7, and CCR9. Analyses of elicited DAF(-/-) Foxp3(+) Tregs showed reduced expression of interferon regulatory factor 8 (IRF-8)/aldehyde dehydrogenase 1 family member A2 (Aldh1a2) and glycoprotein A repetitions predominant/latency-associated protein associated with Treg transforming growth factor-beta production and presentation, as well as integrin beta 6/integrin beta 8 associated with Treg and CD103(+) DC transforming growth factor-beta release. Thus, DAF is required for the properties of CD103(+) DCs and their na ve CD4(+) cell partners that together program tolerance.