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 mice or 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 Foxp3–green fluorescent protein mice. Phenotyping of CD103 dendritic cells (DCs) from the ovalbumin-fed 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 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-β production and presentation, as well as integrin β6/integrin β8 associated with Treg and CD103 DC transforming growth factor-β release. Thus, DAF is required for the properties of CD103 DCs and their naïve CD4 cell partners that together program tolerance.