Interleukin 35 Regulatory B Cells Choi, Jin Kyeong; Egwuagu, Charles E.
Journal of molecular biology,
01/2021, Letnik:
433, Številka:
1
Journal Article
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B lymphocytes play a central role in host immunity. They orchestrate humoral immune responses that modulate activities of other immune cells and produce neutralizing antibodies that confer lasting ...immunity to infectious diseases including smallpox, measles and poliomyelitis. In addition to these traditional functions is the recent recognition that B cells also play critical role in maintaining peripheral tolerance and suppressing the development or severity of autoimmune diseases. Their immune suppressive function is attributed to relatively rare populations of regulatory B cells (Bregs) that produce anti-inflammatory cytokines including interleukin 10 (IL-10), IL-35 and transforming growth factor-β. The IL-35-producing B cell (i35-Breg) is the newest Breg subset described. i35-Bregs suppress central nervous system autoimmune diseases by inducing infectious tolerance whereby conventional B cells acquire regulatory functions that suppress pathogenic Th17 responses. In this review, we discuss immunobiology of i35-Breg cell, i35-Breg therapies for autoimmune diseases and potential therapeutic strategies for depleting i35-Bregs that suppress immune responses against pathogens and tumor cells.
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•i35-Bregs suppress encephalomyelitis and uveitis in mouse models of human uveitis and multiple sclerosis.•i35-Breg cells suppress CNS autoimmune diseases by antagonizing Th1/Th17 responses and inducing expansion of regulatory B and T cells that secrete IL-10 and/or IL-35.•i35-Bregs have distinctive capacity of inducing infectious tolerance and converting conventional B cells to IL-35/IL-10-producing Breg cells.•In B cells, IL-35 signals through IL12Rβ2/IL27Rα and STAT1/STAT3 and IL-35/IL-10 expression requires recruitment of BATF-IRF-4-IRF-8 complex to il12a, ebi3, and il10 loci.•I35-Bregs release IL-35-containing exosomes (i35-Exosomes) and the i35-Exosomes suppress uveitis and encephalomyelitis in mice.
B Cell Function in the Tumor Microenvironment Downs-Canner, Stephanie M; Meier, Jeremy; Vincent, Benjamin G ...
Annual review of immunology,
04/2022, Letnik:
40, Številka:
1
Journal Article
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The tumor microenvironment (TME) is a heterogeneous, complex organization composed of tumor, stroma, and endothelial cells that is characterized by cross talk between tumor and innate and adaptive ...immune cells. Over the last decade, it has become increasingly clear that the immune cells in the TME play a critical role in controlling or promoting tumor growth. The function of T lymphocytes in this process has been well characterized. On the other hand, the function of B lymphocytes is less clear, although recent data from our group and others have strongly indicated a critical role for B cells in antitumor immunity. There are, however, a multitude of populations of B cells found within the TME, ranging from naive B cells all the way to terminally differentiated plasma cells and memory B cells. Here, we characterize the role of B cells in the TME in both animal models and patients, with an emphasis on dissecting how B cell heterogeneity contributes to the immune response to cancer.
The results of recent studies have shown that granulocytic-myeloid derived suppressor cells (G-MDSCs) can secrete exosomes that transport various biologically active molecules with regulatory effects ...on immune cells. However, their roles in autoimmune diseases such as rheumatoid arthritis remain to be further elucidated. In the present study, we investigated the influence of exosomes from G-MDSCs on the humoral immune response in murine collagen-induced arthritis (CIA). G-MDSCs exosomes-treated mice showed lower arthritis index values and decreased inflammatory cell infiltration. Treatment with G-MDSCs exosomes promoted splenic B cells to secrete IL-10 both
and
. In addition, a decrease in the proportion of plasma cells and follicular helper T cells was observed in drainage lymph nodes from G-MDSCs exosomes-treated mice. Moreover, lower serum levels of IgG were detected in G-MDSCs exosomes-treated mice, indicating an alteration of the humoral environment. Mechanistic studies showed that exosomal prostaglandin E2 (PGE2) produced by G-MDSCs upregulated the phosphorylation levels of GSK-3β and CREB, which play a key role in the production of IL-10
B cells. Taken together, our findings demonstrated that G-MDSC exosomal PGE2 attenuates CIA in mice by promoting the generation of IL-10
Breg cells.
•PD-1+ B cells were significantly upregulated in differentiated thyroid tumors.•Long-term stimulation upregulated PD-1/PD-L1 in B cells.•PD-1+ B cells suppressed the proliferation and viability of ...CD4+ and CD8+ T cells.•PD-1+ B cells inhibited autologous T cell expansion via PD-L1-dependent pathway.•Surgery and radioiodine therapy reduced the frequency of PD-1+ B cells.
B cell-mediated regulatory function is instrumental to the maintenance of tolerance, but may also contribute to immune dysfunction during infectious diseases and malignancies. In this study, we investigated a subset of B cells characterized by PD-1 expression. Data showed that these PD-1+ B cells were rare in peripheral blood, but were significantly upregulated in differentiated thyroid tumors. The PD-1+ B cells also expressed significantly higher level of PD-L1. Continuous, but not short-term, anti-Ig/CD40 L stimulation could upregulate the expression of PD-1 and PD-L1 in B cells. In in vitro experiments, PD-1+ B cells significantly suppressed the proliferation of CD4+ and CD8+ T cells and reduced their viability upon CD3/CD28 stimulation, thus suggesting that these PD-1+ B cells presented regulatory functions. However, unlike other IL-10-secreting Breg cell subsets, the PD-1+ B cells did not express high level of IL-10. Instead, it seemed that PD-L1 was instrumental to the suppressive effects mediated by PD-1+ B cells, since the blockade of PD-L1 significantly increased the proliferation and viability of T cells in the coculture. Interestingly, compared to untreated patients with differentiated thyroid tumor, the thyroidectomy and 131I-treated patients presented significantly lower frequencies of PD-1+ B cells. Together, our investigation demonstrated that the PD-1+ B cells possessed regulatory capacity toward T cell responses, and although rare in peripheral blood, they were significantly enriched in thyroid tumors.
Regulatory B cells, A to Z Jansen, Kirstin; Cevhertas, Lacin; Ma, Siyuan ...
Allergy (Copenhagen),
September 2021, Letnik:
76, Številka:
9
Journal Article
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B cells play a central role in the immune system through the production of antibodies. During the past two decades, it has become increasingly clear that B cells also have the capacity to regulate ...immune responses through mechanisms that extend beyond antibody production. Several types of human and murine regulatory B cells have been reported that suppress inflammatory responses in autoimmune disease, allergy, infection, transplantation, and cancer. Key suppressive molecules associated with regulatory B‐cell function include the cytokines IL‐10, IL‐35, and TGF‐β as well as cell membrane‐bound molecules such as programmed death‐ligand 1, CD39, CD73, and aryl hydrocarbon receptor. Regulatory B cells can be induced by a range of different stimuli, including microbial products such as TLR4 or TLR9 ligands, inflammatory cytokines such as IL‐6, IL‐1β, and IFN‐α, as well as CD40 ligation. This review provides an overview of our current knowledge on regulatory B cells. We discuss different types of regulatory B cells, the mechanisms through which they exert their regulatory functions, factors that lead to induction of regulatory B cells and their role in the alteration of inflammatory responses in different diseases.
The increasingly recognized role of different types of B cells and plasma cells in protective and pathogenic immune responses combined with technological advances have generated a plethora of ...information regarding the heterogeneity of this human immune compartment. Unfortunately, the lack of a consistent classification of human B cells also creates significant imprecision on the adjudication of different phenotypes to well-defined populations. Additional confusion in the field stems from: the use of non-discriminatory, overlapping markers to define some populations, the extrapolation of mouse concepts to humans, and the assignation of functional significance to populations often defined by insufficient surface markers. In this review, we shall discuss the current understanding of human B cell heterogeneity and define major parental populations and associated subsets while discussing their functional significance. We shall also identify current challenges and opportunities. It stands to reason that a unified approach will not only permit comparison of separate studies but also improve our ability to define deviations from normative values and to create a clean framework for the identification, functional significance, and disease association with new populations.
•Tregs and Bregs are vital in controlling the immune response.•In periodontitis (PD), Tregs and Bregs become dysregulated or develop plasticity.•Regulatory cells have been shown to be a promising ...therapeutic approach in PD.
Periodontitis (PD), also known as gum disease, is a condition causing inflammatory bone resorption and tooth loss. Regulatory T cells (Tregs) and regulatory B cells (Bregs) are vital in controlling the immune response and hence play a role in infections and peripheral tolerance adjustment. These cells have immunosuppressive and tissue-repairing capabilities that are important for periodontal health; however, in inflammatory circumstances, Tregs may become unstable and dysfunctional, accelerating tissue deterioration. In recent years, Regulatory cell-mediated immunotherapy has been shown to be effective in many inflammatory diseases. Considering the roles of Tregs and Bregs in shaping immune responses, this study aimed to review the published articles in this field to provide a comprehensive view of the existing knowledge about the role of regulatory T and B cells, as well as their therapeutic applications in PD.
IL‐10‐producing regulatory B (Breg) cells are well recognized for maintaining immune tolerance. The impaired Breg cell function with decreased IL‐10‐producing capacity has been found in autoimmune ...diseases, such as rheumatoid arthritis, lupus, and primary Sjogren's syndrome (pSS). However, seldom therapeutic agents targeting Breg cells are available to treat those autoimmune diseases. Here, we showed that acteoside (AC), a caffeoyl phenylethanoid glycoside from a medicinal herb Radix Rehmanniae, could promote IL‐10 production from both human and murine B cells via critically regulating the TLR4/PI3K axis. Moreover, TLR4 was found increased in Breg cells from mice with experimental SS (ESS), a mouse model that recapitulates human pSS. Thus, B cells from the ESS mice were susceptible to AC treatment, showing higher IL‐10‐producing capacity than those from naïve controls. In addition, AC treatment also promoted the production of IL‐10 from TLR4+CXCR4+ plasma cells of ESS mice. Notably, we found that AC was able to enter lymphoid organs upon oral administration. AC treatment effectively increased IL‐10+ B cells in ESS mice and ameliorated disease pathology accompanied by reduced T effector cells, including Th17 and T follicular helper cells in the ESS mice. In conclusion, AC could promote Breg cell function and attenuate ESS pathology in vivo, which may be a promising drug candidate for treating pSS and other autoimmune diseases.
Graphical
Acteoside promotes IL‐10‐producing capacity of B cells in a TLR4/PI3K dependent manner, and thus restores regulatory B cell function during autoimmune progression.
Regulatory B lymphocytes (Bregs) are B cells with well-pronounced immunosuppressive properties, allowing them to suppress the activity of effector cells. A broad repertoire of immunosuppressive ...mechanisms makes Bregs an attractive tool for adoptive cell therapy for diseases associated with excessive activation of immune reactions. Such therapy implies Breg extraction from the patient's peripheral blood,
activation and expansion, and further infusion into the patient. At the same time, the utility of Bregs for therapeutic approaches is limited by their small numbers and extremely low survival rate, which is typical for all primary B cell cultures. Therefore, extracting CD19
cells from the patient's peripheral blood and specifically activating them
to make B cells acquire a suppressive phenotype seems to be far more productive. It will allow a much larger number of B cells to be obtained initially, which may significantly increase the likelihood of successful immunosuppression after adoptive Breg transfer. This comparative study focuses on finding ways to efficiently manipulate B cells
to differentiate them into Bregs. We used CD40L, CpG, IL4, IL21, PMA, and ionomycin in various combinations to generate immunosuppressive phenotype in B cells and performed functional assays to test their regulatory capacity. This work shows that treatment of primary B cells using CD40L + CpG + IL21 mix was most effective in terms of induction of functionally active regulatory B lymphocytes with high immunosuppressive capacity
.
The maternal immune system needs to be tolerant of allogeneic fetal tissue for reproductive success. The regulatory immune cell network plays an essential role in maintaining maternal tolerance to ...the fetus. We herein demonstrate in a green fluorescent protein (GFP)/IL-10 reporter mouse system that unique IL-10-expressing cells exist presumably in chorionic villi within the placenta. Flow cytometric analysis revealed that these IL-10- expressing cells exhibit a unique CD19 negative, CD3 negative, and B220 positive phenotype. Interestingly, these cells were enriched during in vitro culture, but well-known stimuli for T cells and B cells failed to enhance their growth, suggesting that the CD19- CD3- B220+ cells were self renewing. Unexpectedly, in an adoptive cell trans fer experiment, IL-10 production was detected in Sca-1+ CD4+ CD25+ regulatory T cells (Treg). To our knowledge, this is the first report to identify IL-10-producing CD19- CD3- B220+ cells in the fetus. These cells may rep resent a potential progenitor of Sca-1+ Treg or pluripotent precursor cells for immune tolerance.
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