CLIC1 regulates dendritic cell antigen processing and presentation by modulating phagosome acidification and proteolysis.
Intracellular 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.
St Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, New South Wales 2010, Australia.
Kanin
K
Salao
St Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, New South Wales 2010, Australia.
Lele
L
Jiang
St Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, New South Wales 2010, Australia.
Hui
H
Li
St Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, New South Wales 2010, Australia.
Vicky W-W
VW
Tsai
St Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, New South Wales 2010, Australia.
Yasmin
Y
Husaini
School of Physics, University of New South Wales, Sydney, New South Wales 2052, Australia.
Paul M G
PM
Curmi
Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Louise J
LJ
Brown
St Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, New South Wales 2010, Australia.
David A
DA
Brown
St Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, New South Wales 2010, Australia s.breit@amr.org.au.
Samuel N
http://orcid.org/0000-0002-9021-9879
SN
Breit
Acidification; Antigen presentation; CLIC1; Dendritic cells; Phagosome; Proteolysis