IL-27–producing B-1a cells suppress neuroinflammation and CNS autoimmune diseases

Abstract

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. 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. Breg cells identified thus far are largely antigen-specific and derive mainly from B2-lymphocyte lineage. Here, we describe an innate-like IL-27–producing natural regulatory B-1a cell (i27-Breg) in peritoneal cavity and human umbilical cord blood. i27-Bregs accumulate in CNS and lymphoid tissues during neuroinflammation and confers protection against CNS autoimmune disease. 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. 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. 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. 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.

Photoreceptor Cells Constitutively Express IL-35 and Promote Ocular Immune Privilege

“…Other reports found increased IL-27 levels in cerebrospinal fluid (CSF) and active plaques of MS patients, and the local secretion of IL-27 is thought to induce activation of regulatory responses that promote resolution of chronic inflammation in the CNS and to initiate tissue repair [ 12 ]. These results are in line with a recent report that a novel IL-27-producing B-1a population suppresses uveitis and encephalomyelitis by proliferating and sustaining IL-27 production in the retina, brain and spinal cord of mice [ 9 ]. On the other hand, microglia initiate protective immunity in the CNS by promoting vascularization and infiltration of immune cells into the retina [ 13 , 14 ].…”

“…IL-27 (IL-27p28/Ebi3) and IL-35 (IL-12p35/Ebi3) are immunosuppressive cytokines produced by myeloid and lymphoid cells and have been implicated in the suppression of autoimmune diseases [ 1 , 9 , 11 , 16 ]. Surprisingly, IL-27 is constitutively and also inducibly expressed in the retina and contributes to the suppression of ocular inflammatory disease or uveitis [ 17 , 18 ].…”

“…Moreover, expression of IL-27 and IL-35 contiguous to where microglia and photoreceptors reside in the retina, respectively, suggests that these glial (microglia) and specialized neurons (rods and cones) might perform unique functions in the retina that require IL-27 and IL-35. Expression of IL-27 by microglia has been shown to have a double-edged-sword effect on immunity, as the activated M1-like microglia required to initiate protective immunity in the CNS [ 9 , 11 , 32 ] can also exhibit deleterious activities during sustained inflammation or noxious insults as underscored by the suppression of ocular inflammation in mice lacking microglia [ 13 , 14 ]. On the other hand, the M2-like microglia is associated with tissue repair and recovery from injury, and IL-35 regulates the M1/M2 macrophage ratio and promotes microglial M2 polarization and single nucleotide polymorphemic changes in il-12a (SNP rs2243115) correlates with susceptibility to Vogt–Koyanagi–Harada syndrome (VKH), a severe panuveitis with acute onset [ 33 , 34 , 35 ].…”

“…Despite sharing the common Ebi3 subunit, IL-27 and IL-35 are not coordinately regulated, as they can have different functions depending on the physiological context, and they are often produced by distinct cell types. For example, IL-27 is produced mainly by innate B-1a cells in the peritoneal cavity and human umbilical blood, while IL-35 is produced mainly by B-2 cells in the spleen [ 9 , 10 ]. In this study, we have shown that IL-35 is produced predominantly by cells in the photoreceptor layers, while previous reports indicate that IL-27 is produced mainly by microglia [ 11 , 18 ].…”

“…Studies in mouse models of uveitis and MS have established involvement of IL-12, IL-23, IL-27 and IL-35 in initiating or regulating encephalomyelitis and ocular inflammatory diseases. Thus, targeted deletion or neutralization of T cells that produce IL-12 and/or IL-23 or cell therapy based on administering regulatory B cells (Breg) or T cells (Treg) that produce IL-27 or IL-35 has been found to be effective in suppressing experimental autoimmune uveitis (EAU) and experimental autoimmune encephalomyelitis (EAE) that serve as mouse models of uveitis and MS, respectively [ 9 , 10 ].…”