B-1a cells have the dual role of maintaining tolerance to normal tissue proteins and regulating endogenous pathogens that induce high intensity toll-like receptor (TLR) signals in tissues or microbiota ( 2, 4). They express cell-surface CD5 (on B-1a but not B-1b cells), which serves to increase BCR signaling threshold, thereby restricting activation of B-1a cells to very strong signals induced by innate stimuli ( 4). B-1 cells produce natural IgM antibodies, express polyreactive germline B cell receptor (BCR) with limited N-region diversity and are considered as innate lymphocytes ( 3). B-1 cells derive from fetal hematopoietic stem cells in yolk sac or fetal liver, reside primarily in peritoneal cavity (PeC) or umbilical cord blood (CB), and are the earliest B cells to arise during development ( 1, 2). The two B cell lineages in mammals are B-1 and B-2 cells. Consistent with its developmental origin, disease suppression by innate i27-Bregs is neither antigen-specific nor disease-specific, suggesting that i27-Breg would be effective immunotherapy for a wide spectrum of autoimmune diseases. Mutant mice lacking irf4 in B cells exhibit exaggerated increase of i27-Bregs with few i35-Bregs, while mice with loss of irf8 in B cells have abundance of i35-Bregs but defective in generating i27-Bregs, identifying IRF8/BATF and IRF4/BATF axis in skewing B cell differentiation toward i27-Breg and i35-Breg developmental programs, respectively. Furthermore, i27-Breg proliferates in vivo and sustains IL-27 secretion in CNS and lymphoid tissues, a therapeutic advantage over administering biologics (IL-10, IL-35) that are rapidly cleared in vivo.
i27-Breg immunotherapy ameliorated encephalomyelitis and uveitis through up-regulation of inhibitory receptors (Lag3, PD-1), suppression of Th17/Th1 responses, and propagating inhibitory signals that convert conventional B cells to regulatory lymphocytes that secrete IL-10 and/or IL-35 in eye, brain, or spinal cord. i27-Bregs accumulate in CNS and lymphoid tissues during neuroinflammation and confers protection against CNS autoimmune disease. Here, we describe an innate-like IL-27–producing natural regulatory B-1a cell (i27-Breg) in peritoneal cavity and human umbilical cord blood. Breg cells identified thus far are largely antigen-specific and derive mainly from B2-lymphocyte lineage. Thus, loss of Breg function is implicated in development of autoimmune diseases while aberrant elevation of Breg prevents sterilizing immunity, exacerbates infectious diseases, and promotes cancer metastasis.
Regulatory B cells (Breg cells) that secrete IL-10 or IL-35 (i35-Breg) play key roles in regulating immunity in tumor microenvironment or during autoimmune and infectious diseases.
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