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Investigating the phenotype and function of tissue-resident B cells in mouse and human non-lymphoid organs 10.17863/CAM.54791 Suchanek, Ondrej 0000000310485251 Clatworthy, Menna 0000000233409828 B lymphocytes play a central role in humoral immunity but also have antibody-independent functions. Studies to date have focused on B cells within blood and secondary lymphoid organs. This thesis sought to address the question of whether B cells reside in non-lymphoid organs (NLOs), and to determine their phenotype and function. Using intravenous labelling and parabiosis, we identified a population of bona-fide self-renewing, tissue-resident B cells, represented mainly by innate-like CD5+ B-1 cells, across murine NLOs, including lung, liver, kidney and bladder. The size and phenotype of this tissue-resident B-cell subset was influenced by genetic background, age and the microbiome, with an expanded population evident in pet-store mice. Extravascular B cells had less diverse Igh repertoire with fewer N-additions compared to blood, suggesting their prenatal origin. Seeding of these B cells into NLOs was independent of their antigen specificity. Using strains of genetically modified mice with higher (PI3Kδ E1020K-B, Siglec-G-/-) or lower (μMT-) numbers of tissue-resident B cells in NLOs, we tested the function of these cells in the context of urinary tract infection. The number of tissue-resident B cells inversely correlated with bacterial clearance suggesting that B cells negatively regulate anti-microbial responses. Tissue-resident B cells were spatially co-localised with macrophages and had a profound effect on macrophage polarisation, promoting an anti-inflammatory M2 phenotype, an effect at least partially driven via interleukin (IL)-10. Finally, in human NLOs we found a similar enrichment for non-naïve less diverse B cells when compared to blood and spleen, with indices for innate-like and regulatory phenotype. In conclusion, these data identify a critical role for tissue-resident B cells in modulating organ immunity, determining inflammatory 'set-point' of resident and recruited myeloid cells, with important clinical implications. University of Cambridge 2020-03-27 Thesis Doctoral Doctor of Philosophy (PhD) eng Wellcome Trust https://www.repository.cam.ac.uk/handle/1810/307698 https://www.repository.cam.ac.uk/bitstreams/848c79d3-53c7-45c2-8f2b-a1fef8b33c17/download 4eeb0a6bf437acc323e84bca301f9c8e https://www.repository.cam.ac.uk/bitstreams/a8759ba6-44d1-4624-bee9-f0a6bea31a16/download 353adac0d1ebdfd65ab16480263c3c87 http://purl.org/NET/rdflicense/allrightsreserved B lymphocyte tissue-resident macrophage polarisation kidney