#2585 Human kidneys house innate-like B cells that transcriptomically mirror murine B-1 cells and change with age

Abstract Background and Aims There is growing evidence that B cells (memory and innate-like) reside in non-lymphoid organs where they play an important role for generating local immune responses or maintaining tolerance [1]. Several studies observed accumulation of innate-like self-reactive B cells in human kidneys following an injury or transplant rejection, associated with progressive organ dysfunction [2,3]. However, the origin of these B cells is unknown. Here, were investigated whether human kidneys house B cells in homeostasis and how they change with donor age. Method We examined the number, phenotype and clonality of B cells in human kidneys that were perfused to remove circulating cells, and in matched splenic tissue obtained from the same transplant donor (N = 19, median age 56 years (range: 18–80). Suspensions from homogenized organs were analyzed using a 35-marker mass cytometry panel and single-cell RNA sequencing. B cells were also sorted for bulk BCR-sequencing. Results At steady state, human kidneys house B cells enriched for non-naïve (CD27+IgD− and double-negative) subsets when compared to spleen or younger donors. The renal cortex harbours ten times more B cells per gram of tissue than medulla. In contrast to spleen, B cell count and B:T cell ratio in renal cortex significantly increase with age (Fig. A). Kidney B-cell immune repertoire is less diverse but also less mutated than spleen, suggesting the presence of innate-like B cells. Indeed, single-cell-RNA sequencing analysis reveals that large proportion of non-naïve kidney B cells belongs to IgM/IgA memory subset with transcriptomic similarity to murine B-1 cells (not marginal-zone B cells) (Fig. B). Conclusion Our study shows that under homeostatic conditions, human kidneys harbour a large proportion of IgM/IgA memory B cells with innate-like features that transcriptomically mirror murine B-1 cells and increase with age. This B cell subset might further expand following an injury and fuel local immunopathology and organ dysfunction as observed by previous studies [2,3]. Hence, selective targeting of these innate-like B cells could be an important therapeutic strategy.