Figure 2. Niche-specific B-1 cell heterogeneity.

B-1 cells from distinct anatomical regions display functional heterogeneity in IgM antibody production, arising from both extrinsic microenvironmental factors and intrinsic differences. Peritoneal cavity (PerC) B-1 cells secrete less IgM constitutively compared to B-1 cells from spleen, bone marrow, perivascular adipose tissue (PVAT), and adventitial tertiary lymphoid organs (ATLO). In the PerC, PC-1 expression distinguishes B-1a cells with high capacity to produce IgM (PC-1^lo), from those with low capacity to produce IgM (PC-1^hi). The src family kinase Lck also maintains the hyporesponsiveness of PerC B-1a cells. Additional heterogeneity in the PerC B-1 population is evidenced by distinct immunoglobulin heavy chain (IgH) repertoires expressed by PerC B-1a vs B-1b cells, with PerC B-1a cells expressing more germline sequences that lack N-additions and a preference for V_H11/V_H12 family gene segments. In contrast, splenic B-1a cells produce more IgM constitutively in a manner dependent on the transcription factor IRF4, and the splenic B-1a IgH repertoire contains more N-additions and greater VDJ gene segment diversity. The transcription factor Id3 inhibits B-1b cell number and consequently IgM antibody production. Bone marrow (BM) B-1 cells also produce more IgM constitutively compared to PerC B-1 cells, and IL-5 has been shown to maintain the BM IgM-secreting cell population. The PVAT contains type 2 innate lymphoid cells (ILC-2) that secrete IL-5 in response to IL-33. Whether ILC-2 derived IL-5 is responsible for maintaining the high constitutive IgM production that occurs in PVAT is unknown. ATLO contain an abundance of IL-10 producing B-1b cells. B-1 cell trafficking between these compartments relies on adhesion molecules. The chemokine receptor CXCR5 mediates B-1 cell trafficking between the spleen and the PerC. CXCR4 mediates B-1 cell migration to the bone marrow. CCR6 and L-selectin mediate B-1 localization to the PVAT and aorta.