MO064TISSUE-RESIDENT B CELLS DETERMINE SUSCEPTIBILITY TO URINARY TRACT INFECTION BY ORCHESTRATING MACROPHAGE POLARISATION

Abstract

Abstract Background Urinary tract infection (UTI) is an important clinical problem. More than half of women and 1 in 10 men will be affected during their lifetime. Many of these affect the lower urinary tract but recurrent pyelonephritis can lead to scarring and chronic kidney disease. There is an increasing appreciation that tissue-resident immune cells, such as macrophages, play an important role in defence against infection, but only little is known about B lymphocytes in this context. Here we sought to address the question of whether B cells reside in the kidney and bladder in homeostasis and to determine their phenotype and contribution to local organ immunity. Methods and Results Using intravenous labelling and parabiosis, we identified a population of bona-fide self-renewing, tissue-resident B cells that included non-naïve and innate-like CD5+ B-1 cells, in murine kidneys and urinary bladder (but also in liver and lung). The size and phenotype of this B cell subset was influenced by genetic background, age, and microbiome, with an expanded population evident after co-housing with pet-store mice. Although kidney B cells had less diverse Igh repertoire compared to blood, their seeding was largely independent of their B-cell receptor specificity. In human kidneys we found a similar enrichment for non-naïve B cells compared to blood and spleen. Using two strains of genetically modified mice with higher (PI3KδE1020K-B) or lower (μMT-) numbers of tissue-resident B cells, we tested the function of these cells during UTI. Surprisingly, the number of tissue-resident B cells inversely correlated with bacterial clearance. We found that these B cells were spatially co-localised with kidney macrophages and skewed their polarization towards an anti-inflammatory M2 phenotype, leading to reduced anti-microbial responses. This effect was, at least in part, driven via IL-10. Conclusion In conclusion, our data identify a critical role for tissue-resident B cells in modulating local immunity in the urinary tract, determining the inflammatory ‘set-point’ of resident and recruited myeloid cells, with important clinical implications for the use of B-cell depleting therapies and conditions such as infection, transplant rejection, fibrosis or autoimmunity. Graphical Abstract