A role for CMTM7 in BCR expression and survival in B-1a but not B-2 cells Yanfei Zhang 1 , Ji-Yang Wang 2–4 and Wenling Han 1 1 Peking University Center for Human Disease Genomics, Department of Immunology, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China 2 Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama 230-0045, Japan 3 Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan 4 Department of Immunology, Shanghai Medical College, Shanghai 200032, China Correspondence to: W. Han; E-mail: hanwl@bjmu.edu.cn Received 28 May 2013, accepted 9 August 2013 Abstract B-1 cells are an important cell population for the production of natural antibodies and front-line host defense. Here, we show that the MARVEL-domain-containing membrane protein CMTM7 (CKLF-like MARVEL transmembrane domain-containing 7) plays a critical role in BCR expression and survival in B-1a cells. We analyzed lymphocyte development in Rag1 −/− mice reconstituted with Cmtm7 fox/+ fetal liver cells because of the unexpected lethality of the Cmtm7 fox/+ heterozygotes. We found a mild reduction of serum IgM and a signifcantly reduced B-1a population in the peritoneal cavity of Rag1 −/− mice reconstituted with Cmtm7 fox/+ cells compared with those reconstituted with wild-type (WT) cells. The reduction of B-1a cells in Cmtm7 fox/+ mice was associated with reduced BCR expression and increased spontaneous cell death in these cells. In addition, both B-1a and B-1b cells derived from Cmtm7 fox/+ fetal liver cells contained a lower frequency of cells capable of spontaneously differentiating into IgM-secreting plasma cells than did those derived from WT fetal liver cells. Furthermore, Cmtm7 fox/+ B-1a and B-1b cells responded poorly to LPS-induced proliferation. In striking contrast to the defects in B-1 cells, Cmtm7 fox/+ B-2 cells did not show obvious abnormalities when compared with WT B-2 cells. These results demonstrate a specifc role for CMTM7 in BCR expression and survival in B-1a cells. Keywords: B-1a, BCR expression, cell death, CMTM7, natural IgM Introduction B-1 cells are a minor but important subset of B cells, which can be distinguished from conventional B cells by their surface markers, anatomic location and self-replenishing capacity. In mice, B-1 cells mainly exist in peritoneal and pleural cavities, and a small fraction of B-1 cells are also present in the spleen. On the basis of their CD5 expres- sion, B-1 cells can be divided into two subsets: CD5 + B-1a and CD5 − B-1b cells (1–3). B-1a cells are believed to be the major source of natural antibodies in normal unimmunized mice. These antibodies are mainly of the IgM isotype, and can be produced independently of exogenous antigenic stimulation (4, 5). The peripheral localization and the capac- ity of secreting natural antibodies make B-1 cells a critical contributor to the frst-line host defense against microbial infections before an adaptive immune response is estab- lished (6–8). Natural antibodies are usually weakly self-reactive. Therefore, B-1 cells that secrete these antibodies are potential contributors to the development of autoimmune diseases. In fact, elevated numbers of B-1a cells are often associated with autoimmunity both in human and mouse models. Increased B-1 cells have been reported in patients with Sjogren’s syndrome (9) and rheu- matoid arthritis (10). In addition, increased B-1 cells have been found in the (NZBxNZW) F1 murine lupus model and its deriv- ative NZM241 (11, 12). A large number of experiments have revealed that BCR signaling is crucial for B-1 cell development and maintenance. Impaired BCR signaling usually leads to sub- stantial depletion or decrease of B-1 cells, such as in mice with a Btk mutation (13), while deletion of the negative regulators of BCR signaling often results in an increase of B-1 cells, such as in Siglec-G-defcient mice (14, 15), FcγRIIb-defcient mice (16), motheaten mice and the viable motheaten mice with mutation © The Japanese Society for Immunology. 2013. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com International Immunology, Vol. 26, No. 1, pp. 47–57 doi:10.1093/intimm/dxt042 Advance Access publication 30 September 2013 Downloaded from https://academic.oup.com/intimm/article/26/1/47/728331 by guest on 11 July 2022