B10 cell
B10 cells are a sub-class of regulatory B cells (Breg cell) that are involved in inhibiting immune responses in both humans and mice.[1][2][3] B10 cells are named for their ability to produce inhibitory interleukin: Interleukin-10 (IL-10).[4][5] One of their unique abilities is that they suppress the innate and adaptive immune signals, making them important for regulating the inflammatory response. Like the B cell, the B10 cell requires antigen specific binding to the surface of CD5 receptor to elicit a response from the T cell. Once an antigen binds to the CD19 receptor, immediate downregulation in B-cell receptor (BCR) signal expression occurs and mediates the release of IL-10 cytokines.[3] In mice and humans, B10 cells are distinguishable in their expression of measurable IL-10 due to the lack of unique cell surface markers expressed by regulatory B cells.[1][3] However, IL-10 competence is not limited to any one subset of B cells.[3] B10 cells do not possess unique phenotypic markers or transcription factors for further identification.[6] B10 cells predominantly localize in the spleen, though they are also found in the blood, lymph nodes, Peyer's patches, intestinal tissues, central nervous system, and peritoneal cavity.[1] B10 cells proliferate during inflammatory and disease responses.[3]
History
[edit]Sauropsida divergence was coincident with the emergence of B10.[7] B10 markers have been expressed since this divergence event, including CD19, CD1d, IL-21, and CD5 markers.[7] CD24, a human B10 marker, is exclusive to higher vertebrates and is absent in Vombatus and the organisms that diverged prior.[7]
The B10 cell was first characterized in 2008, as a different subset of B cells in mice. By inducing hypersensitive T cells, the immune response of the mice was over-expressed.[3] When compared to the wild type or normal expression of antigen receptors, the B cells bound to CD19 molecules actually decreased inflammation. The in vivo model demonstrated that a new characterization of B cell was producing IL-10 which was later defined as the B10 effector (B10eff) cells.
Development and differentiation
[edit]B10 cells are presumed to originate from B10 progenitor (B10pro) cells, which can mature into B10eff cells with lipopolysaccharide (LPS) stimulation or CD40 litigation.[1][8] In mice, B10eff cells (derived from B10 cells) actively secrete IL-10, whereas competency for IL-10 expression in B10pro cells must be induced by ex vivo stimulation.[1] BCR signals are fundamental to the development of B10pro cells which can develop into B10eff cells in the presence of CD40 signals, LPS, or IL-21.[1] Some B10eff cells further develop into Ab-secreting plasma cells.[1] B10 cell development is antigen (Ag)-regulated through BCR signaling pathways which select for Ag-specific B10 cells and stimulate IL-10 competency.[1][3] In vitro identification of IL-10-competent cells can occur by stimulation of B cells using PMA and ionomycin.[3]
Within the spleen of C57B1/6 mice, B10 cells comprise 1-3% (and B10+B10pro cells comprise 3-8%) of B cells.[3][9] B10pro cell numbers are comparatively more consistent than B10 cells during immune responses.[3] The general phenotype of B10 splenic cells is IgMhi IgDlo CD19hi MHC-IIhi CD21int/hi CD23lo CD24hi CD43+/- CD93-.[3] Characteristics of this phenotype are similar to immature transitional B cells, marginal zone B cells, and peritoneal B1 cells.[3] Peritoneal B10 cells share a similar phenotype but express lower levels of CD1d.[3] Mouse B10 cells in the spleen are enriched in the B cell subset CD1dhiCD5+, whereas human B10 and B10pro peripheral blood cells are enriched in the B cell subset CD24hiCD27+.[6]
Function
[edit]BCR-antigen interactions and BCR signaling facilitate antigen specificity and reactivity of B10 cells.[3] B10 cell germline BCRs interact with and present antigens to respective CD4+ T cells.[3] These cognate interactions are dependent on MHC-II and CD40, and encourage IL-10 production and enable B10 cells to suppress macrophage function.[3][6] While cognate CD4+ T cell and B10 cell interactions are critical for B10eff cell functioning, T cells are not.[6] The anti-inflammatory cytokine IL-10 suppresses innate and adaptive immune signals by prohibiting T cell activation, in addition to IFN-γ and Th17 cytokine responses.[1][3] Another cytokine, IL-21, regulates B10eff cell functionality in its integral role to the expansion of B10 cells and secretion of B10eff cells in autoimmune responses.[1]
By a similar regulatory mechanism, the development of B10pro cells is inhibited by TGF-β and IFN-γ.[1] Through their inhibitory effects, B10 cells interfere with antigen-presenting abilities, the production of cytokines, and the activation of dendritic cells.[1] In addition, their secretion of IL-10 can interfere with the phagocytosis, the activation of macrophages, and the production of cytokines and nitric oxide (NO). [1] IL-10 production is regulated, as is the functioning of local macrophages and Ag-specific T cells.[1] By this specificity, IL-10 is delivered to sites of inflammatory and immune response.[3] CpG oligonucleotides promote IL-10 production in competent B10 cells.[1][3] Similarly, innate signals such as IL-1β, IL-6, IL-33, IL-35, TLR signals, infection, and apoptotic cells may proliferate B10 and B10eff cells.[1][3] In the peripheral blood of patients with autoimmune diseases, B10 cell numbers are typically expanded.[6]
Therapeutic potential
[edit]B10 cells have been studied in mouse models on account of their therapeutic relevance to autoimmune disease.[3] In mouse models, the introduction of additional B10 cells during disease onset can mitigate and accelerate disease-related symptoms and progression.[3] Purified B10 cells of subsets including CD1dhiCD5+ B cells and peritoneal cavity B cells demonstrate suppressive effects for Ag-specific responses especially.[1][10] Therapeutic potential for B10 cells was first revealed by the Londei laboratory through induced B cell-expression of IL-10, then later by studies using B10eff cell expansion, both instances of which demonstrated therapeutic effects in the context of disease initiation and progression.[1] Autoimmune disease and cancer treatments are possible through either the preferential expansion or depletion of B10 cells.[6][11]
Disease progression in patients with autoimmune diseases such as lupus or rheumatoid arthritis can commence with insufficient B10 cell numbers.[1] Moreover, B10 cell expansion in the absence of autoimmune-related production of inflammatory cytokine factors provides potential for immune response, allergy, and transplant rejection treatment.[1] Agonistic CD40 antibodies enable in vivo B10 cell expansion, though unwanted responses from additional immune cells may transpire.[6] Ex vivo B10 cell expansion is also possible, though this method is limited in expansion methods, magnitude, and time.[6] Induced B10 cell expansion in esophageal squamous cell carcinoma (ESCC) patients and subsequent elevated IL-10 production support the role of B10 cells in regulating disease progression, specifically through restrained inflammatory responses.[3][4] As such, in adequate quantities, B10 cells can both regulate and treat diseases.[6]
B10 cells are prevalent in the human solid tumor and peritumoral tissues of several cancers, including lung, hepatocellular carcinoma, and breast cancers.[12] Their ability to promote cancer growth is attributed to immunosuppression mechanisms through innate and adaptive immune responses.[12] B10 cell depletion can amplify cellular, innate, and humoral immune system responses and might aid in immune responses to cancer therapy, infectious diseases, and vaccines.[1] The depletion of B10 cells enables a more rapid immune response and can improve pathogen clearance.[3] Further, inhibited B10 cell functioning can improve anticancer responses.[3] The preferential depletion of B10 cells provides therapeutic potential for enhanced anticancer responses due to the intrinsic ability of B10 cells to impede antitumor immune responses.[3]
References
[edit]- ^ a b c d e f g h i j k l m n o p q r s t u Tedder TF (February 2015). "B10 cells: a functionally defined regulatory B cell subset". Journal of Immunology. 194 (4): 1395–1401. doi:10.4049/jimmunol.1401329. PMID 25663677. S2CID 207430556.
- ^ Candando KM, Lykken JM, Tedder TF (May 2014). "B10 cell regulation of health and disease". Immunological Reviews. 259 (1): 259–272. doi:10.1111/imr.12176. PMC 4049540. PMID 24712471.
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z Lykken JM, Candando KM, Tedder TF (October 2015). "Regulatory B10 cell development and function". International Immunology. 27 (10): 471–477. doi:10.1093/intimm/dxv046. PMC 4817073. PMID 26254185.
- ^ a b Mao Y, Wang Y, Dong L, Zhang Q, Wang C, Zhang Y, et al. (September 2019). "Circulating exosomes from esophageal squamous cell carcinoma mediate the generation of B10 and PD-1high Breg cells". Cancer Science. 110 (9): 2700–2710. doi:10.1111/cas.14122. PMC 6726703. PMID 31276257.
- ^ Liu J, Chen X, Hao S, Zhao H, Pang L, Wang L, et al. (October 2019). "Human chorionic gonadotropin and IL-35 contribute to the maintenance of peripheral immune tolerance during pregnancy through mediating the generation of IL-10+ or IL-35+ Breg cells". Experimental Cell Research. 383 (2): 111513. doi:10.1016/j.yexcr.2019.111513. PMID 31362000. S2CID 198998443.
- ^ a b c d e f g h i Kalampokis I, Yoshizaki A, Tedder TF (2013-02-11). "IL-10-producing regulatory B cells (B10 cells) in autoimmune disease". Arthritis Research & Therapy. 15 (Suppl 1): S1. doi:10.1186/ar3907. PMC 3624502. PMID 23566714.
- ^ a b c Mickael ME, Bieńkowska I, Sacharczuk M (May 2022). "An Update on the Evolutionary History of Bregs". Genes. 13 (5): 890. doi:10.3390/genes13050890. PMC 9141580. PMID 35627275.
- ^ Poe JC, Smith SH, Haas KM, Yanaba K, Tsubata T, Matsushita T, Tedder TF (2011-07-25). "Amplified B lymphocyte CD40 signaling drives regulatory B10 cell expansion in mice". PLOS ONE. 6 (7): e22464. Bibcode:2011PLoSO...622464P. doi:10.1371/journal.pone.0022464. PMC 3143148. PMID 21799861.
- ^ Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, et al. (January 2011). "Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells". Blood. 117 (2): 530–541. doi:10.1182/blood-2010-07-294249. PMC 3031478. PMID 20962324.
- ^ Maseda D, Smith SH, DiLillo DJ, Bryant JM, Candando KM, Weaver CT, Tedder TF (February 2012). "Regulatory B10 cells differentiate into antibody-secreting cells after transient IL-10 production in vivo". Journal of Immunology. 188 (3): 1036–1048. doi:10.4049/jimmunol.1102500. PMC 3262922. PMID 22198952.
- ^ Horikawa M, Minard-Colin V, Matsushita T, Tedder TF (November 2011). "Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice". The Journal of Clinical Investigation. 121 (11): 4268–4280. doi:10.1172/JCI59266. PMC 3204847. PMID 22019587.
- ^ a b Wu H, Su Z, Barnie PA (January 2020). "The role of B regulatory (B10) cells in inflammatory disorders and their potential as therapeutic targets". International Immunopharmacology. 78: 106111. doi:10.1016/j.intimp.2019.106111. PMID 31881524. S2CID 209500182.