Abstract

The inhibitory immunoreceptor SIRP is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRP interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRP on B1 lymphocytes, a non-conventional subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRP signaling (SIRP{Delta}CYT mice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective we investigated the involvement of SIRP signaling in atherosclerosis development. Bone marrow (SIRP{Delta}CYT>LDLR-/-) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRP as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRP as a potential therapeutic target in atherosclerosis.