Abstract
ABSTRACTIntracellular chloride channel protein 1 (CLIC1) participates in inflammatory processes by regulating macrophage phagosomal functions such as pH and proteolysis. Here, we sought to determine if CLIC1 can regulate adaptive immunity by actions on dendritic cells (DCs), the key professional antigen presenting cells. To do this, we first generated bone marrow-derived DCs (BMDCs) from germline CLIC1 gene-deleted (CLIC1−/−) and wild-type (CLIC1+/+) mice, then studied them in vitro and in vivo. We found phagocytosis triggered cytoplasmic CLIC1 translocation to the phagosomal membrane where it regulated phagosomal pH and proteolysis. Phagosomes from CLIC1−/− BMDCs displayed impaired acidification and proteolysis, which could be reproduced if CLIC1+/+, but not CLIC1−/− cells, were treated with IAA94, a CLIC family ion channel blocker. CLIC1−/− BMDC displayed reduced in vitro antigen processing and presentation of full-length myelin oligodendrocyte glycoprotein (MOG) and reduced MOG-induced experimental autoimmune encephalomyelitis. These data suggest that CLIC1 regulates DC phagosomal pH to ensure optimal processing of antigen for presentation to antigen-specific T-cells. Further, they indicate that CLIC1 is a novel therapeutic target to help reduce the adaptive immune response in autoimmune diseases.
Highlights
Antigen presentation is a multiple step processes by which antigen presenting cells (APCs), including macrophages and dendritic cells (DCs), ingest, process and present exogenous antigens, in a complex with MHC class II molecules, to T-cells
We show that in resting bone marrow-derived DCs (BMDCs), chloride channel protein 1 (CLIC1) is widely distributed in the cytoplasm in punctate vesicle-like structures similar to those we have previously identified in macrophages (Jiang et al, 2012)
CLIC1 is present on BMDC phagosomal membranes To determine the subcellular localization of CLIC1 in BMDCs, we have used immunofluorescence confocal microscopy
Summary
Antigen presentation is a multiple step processes by which antigen presenting cells (APCs), including macrophages and dendritic cells (DCs), ingest, process and present exogenous antigens, in a complex with MHC class II molecules, to T-cells. If uptake is via phagocytosis, proteolysis of the antigen is initiated by endopeptidases, to fragment the native protein This is followed by sequential trimming of the peptide ends by amino and carboxypeptidases. This helps to generate small peptides that have the required lengths of 18-20 amino acids (Blum and Cresswell, 1988; Deussing et al, 1998) to sit in the antigen binding groove on MHC class II molecules. The invariant chain of MHC II undergoes selective proteolytic cleavage of li, which occupies the antigen binding groove This cleavage event allows for exogenous peptide loading and formation of the MHC II-peptide complex (Busch et al, 2005; Cresswell, 1996), which is transported to the plasma membrane of APCs
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