CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP

Chizuru Akatsu; Kenro Shinagawa; Nobutaka Numoto; Zhihong Liu; Ayse Konuskan Ucar; Mohammad Aslam; Shirly Phoon; Takahiro Adachi; Koji Furukawa; Nobutoshi Ito; Takeshi Tsubata

doi:10.1084/jem.20160560

CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP

J Exp Med. 2016 Nov 14;213(12):2691-2706. doi: 10.1084/jem.20160560. Epub 2016 Oct 24.

Authors

Affiliations

¹ Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
² Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
³ Emergency Department, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, China.
⁴ Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8566, Japan.
⁵ 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.
⁶ 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.

Abstract

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 CD72^c, a lupus-susceptible allele, binds to Sm/RNP less strongly than that of lupus-resistant CD72^a Reduced binding of CD72^c is 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antibody Formation / immunology
Antigens, CD / chemistry
Antigens, CD / metabolism*
Antigens, Differentiation, B-Lymphocyte / chemistry
Antigens, Differentiation, B-Lymphocyte / metabolism*
B-Lymphocytes / immunology*
Crystallography, X-Ray
Endocytosis
Female
Ligands
Lupus Erythematosus, Systemic / immunology*
Lupus Erythematosus, Systemic / pathology
Mice, Inbred C57BL
Models, Molecular
Phosphorylation
Protein Binding
Protein Domains
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
Ribonucleoproteins, Small Nuclear / metabolism*
Signal Transduction
Static Electricity
Surface Plasmon Resonance
Toll-Like Receptor 7 / metabolism*

Substances

Antigens, CD
Antigens, Differentiation, B-Lymphocyte
CD72 antigen, mouse
Ligands
Ribonucleoproteins, Small Nuclear
Toll-Like Receptor 7
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Ptpn6 protein, mouse

Associated data

PDB/1FM5
PDB/5B1R