Investigating the phenotype and function of tissue-resident B cells in mouse and human non-lymphoid organs

Abstract

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.