ABC signature in partial recombination activating gene (RAG) deficiency and chronic TLR stimulation 4662

Abstract Description Background. CD11c+Tbet+ age-associated B cells (ABCs) are IFNg and TLR7/9 sensitive and expand transiently during normal anti-viral response but sustained in disease, such as in patients with monogenic immune dysregulation. Mice with partial recombination activating gene 1 (RAG1) deficiency (pRD) allow close examination ABC-like populations in immune dysregulation and chronic infections. Aims. To contrast B cell subsets with ABC signature in the Rag1R972Q/R972Q mouse model with pRD (mut) to wild type mice (wt) at baseline and with chronic TLR stimulation. Methods. Wt and mut mice were evaluated at baseline and after regular stimulation with TLR7 agonist mimicking viral infections. Splenic B cells were assessed by scRNA/CITE/BCR-seq. Results. A cluster enriched in B cells with ABC signature was defined via transcriptome and CITE-seq profile in wt and mut mice with or without chronic TLR stimulation. Conventional ABC expansion was most notable in TLR7-stimulated mut vs wt mice. A preexisting pool of B cell were identified with “pseudo-ABC phenotype” at baseline in mut mice, showing the high cell surface expression of transitional B cell marker CD93; these cells also express plasma cell marker CD138. Conclusions. A transitional B cell population with ABC-like characteristics persisted in pRD mice at baseline with propensity to become plasma cell and potential for polyreactivity. The pathological relevance of these cells is yet to be determined. Funding Sources NIH 1R01AI153830 Topic Categories Immune Mechanisms of Human Disease (HUM)