Partial RAG deficiency induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells

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CD21low CD11c+ T-bethigh B cells are frequently expanded in various autoimmune disorders, indicating their potential role in autoimmunity. Patients with partial RAG deficiency (pRD) are characterized by humoral autoimmunity, suggesting breach in tolerance mechanisms and subsequent expansion of autoreactive B cell clones.By studying B cell development and subset specific BCR repertoires in a cohort of pRD patients, we found that reduced RAG activity impinges on peripheral tolerance. Tolerance defect is a result of the generation of a restricted primary B cell repertoire and associated with persistent antigenic stimulation and an inflammatory milieu with elevated level of B cell activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, and remarkable expansion of CD21low CD11c+ T-bethigh B cells. Self-reactive clones - identified by single cell cloning of paired heavy and light immunoglobulin chains – persist, expand, and undergo somatic diversification.By investigating a mouse model of pRD (rag1R972Q/R972Q), we detected spontaneous expansion of CD11c+ T-bethigh “age associated B cells” (ABCs) in various lymphoid tissues. Gene expression profiling of splenic B cells by single-cell RNA and paired heavy and light immunoglobulin sequencing revealed imprinted alterations in the epigenetic status of peripheral B cells. Our findings demonstrate that B cell compartment in pRD is dominated with the T-bethigh CD21low ABC-like B cells that have a unique gene expression profile and BCR repertoire that may lead to the B cell dysregulation occurring in pRD patients.