Nitric-oxide synthase 2 interacts with CD74 and inhibits its cleavage by caspase during dendritic cell development.
Dendritic cells (DC) are professional antigen-presenting cells that possess specific and efficient mechanisms to initiate immune responses. Upon encounter with pathogens, immature DC will go through a maturation process that converts them to highly immunogenic mature DC. Despite the fact that nitric oxide (NO) was produced in large amounts in maturing DC, it is still unclear whether NO is the key molecule that initiates and enhances DC maturation and T cell proliferation, respectively. Here, we report that NO donor and overexpression of either nitric-oxide synthase 2 (NOS2) or nitric-oxide synthase 3 (NOS3) alone can induce surface expression of major histocompatibility complex class II (MHC II) and both the essential co-stimulatory molecules CD80 and CD86 in immature DC. Consistently, NO donor-treated immature DC were capable of enhancing T cell proliferation in vitro in the absence of lipolysaccharide. Interestingly, NOS2 interacts with CD74 (the MHC II-associated invariant chain), and the degradation of CD74 by caspases in immature DC was inhibited upon treatment with NO donor. Because the trafficking of MHC II is CD74-dependent, the increase in cell surface localization of MHC II in maturing DC is in part due to the increase in CD74 protein expression in the presence of NOS2 and NO.
Huang
Dachuan
D
Laboratory of Membrane Trafficking and Immunoregulation, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.
Cai
Deyu Tarika
DT
Laboratory of Membrane Trafficking and Immunoregulation, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.
Chua
Rong Yuan Ray
RYR
Laboratory of Membrane Trafficking and Immunoregulation, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.
Kemeny
David Michael
DM
Immunology Programme, National University of Singapore, Singapore 117597, Republic of Singapore.
Wong
Siew Heng
SH
Laboratory of Membrane Trafficking and Immunoregulation, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore; Immunology Programme, National University of Singapore, Singapore 117597, Republic of Singapore. Electronic address: micwsh@nus.edu.sg.
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D000949:Histocompatibility Antigens Class II; D020030:Nitric Oxide Donors; C045084:invariant chain; D052247:Nitric Oxide Synthase Type II; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1