Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice

Abstract

Abstract Central B cell tolerance, the process responsible for mitigating the development of autoreactive B cells, has been extensively studied in mice, while little is known of how human B cells are tolerized in the bone marrow due to the inability to phenotypically distinguish autoreactive and non-autoreactive immature B cells and the difficulty in accessing fresh human bone marrow biopsies. Using a human immune system mouse model where all human Igk+ B cells are autoreactive and therefore tolerized in the bone marrow, we show that human autoreactive immature B cells are phenotypically different from non-autoreactive due to the differential expression of CD69, CD81, CXCR4 and other surface glycoproteins, while also exhibiting lower activation of ERK. Upon treatment of human immune system mice and autoreactive mice with a CXCR4 antagonist we show that signaling through this receptor is necessary to prevent both human and mouse autoreactive B cell clones to egress the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance.