CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP.
Toll-like receptor 7 (TLR7) plays an essential role in development of systemic lupus erythematosus by co-stimulating B cells reactive to the endogenous TLR7 ligand Sm/ribonucleoprotein (RNP), a crucial lupus self-antigen. However, how the TLR7-mediated autoimmune response is regulated is not yet known. In this study, we demonstrate that CD72, an inhibitory B cell co-receptor known to prevent development of lupus, recognizes Sm/RNP at the extracellular C-type lectin-like domain (CTLD) and specifically inhibits B cell response to Sm/RNP. Moreover, the CTLD of CD72c, a lupus-susceptible allele, binds to Sm/RNP less strongly than that of lupus-resistant CD72aReduced binding of CD72cis supported by x-ray crystallographic analysis that reveals a considerable alteration in charge at the putative ligand-binding site. Thus, CD72 appears to specifically inhibit B cell response to the endogenous TLR7 ligand Sm/RNP through CTLD-mediated recognition of Sm/RNP, thereby preventing production of anti-Sm/RNP antibody crucial for development of lupus.
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
Chizuru
0000-0002-6180-2029
C
Akatsu
Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
Kenro
0000-0001-9435-9679
K
Shinagawa
Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
Nobutaka
N
Numoto
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.|Emergency Department, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, China.
Zhihong
Z
Liu
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
Ayse Konuskan
AK
Ucar
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
Mohammad
M
Aslam
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
Shirly
S
Phoon
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
Takahiro
T
Adachi
Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8566, Japan.
Koji
0000-0002-5701-2497
K
Furukawa
Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan tsubata.imm@mri.tmd.ac.jp ito.str@tmd.ac.jp.
Nobutoshi
N
Ito
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan tsubata.imm@mri.tmd.ac.jp ito.str@tmd.ac.jp.
Takeshi
T
Tsubata
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D018360:Crystallography, X-Ray; D004705:Endocytosis; D005260:Female; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D055672:Static Electricity; D020349:Surface Plasmon Resonance; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C513972:CD72 antigen, mouse; D008024:Ligands; D017411:Ribonucleoproteins, Small Nuclear; D051199:Toll-Like Receptor 7; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse