B10 cell

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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 illicit 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]

Contents

History

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

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

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

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]

Related Research Articles

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. Additionally, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the 'B' stands for bursa and not bone marrow as commonly believed.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Memory B cell</span>

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in Homo sapiens

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">CD19</span> Biomarker for B cell lineage

B-lymphocyte antigen CD19, also known as CD19 molecule, B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19. In humans, CD19 is expressed in all B lineage cells. Contrary to some early doubts, human plasma cells do express CD19, as confirmed by others. CD19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.

B1 cells are a sub-class of B cell lymphocytes that are involved in the humoral immune response. They are not part of the adaptive immune system, as they have no memory, but otherwise, B1 cells perform many of the same roles as other B cells: making antibodies against antigens and acting as antigen-presenting cells. These B1 cells are commonly found in peripheral sites, but less commonly found in the blood. These cells are involved in antibody response during an infection or vaccination.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

<span class="mw-page-title-main">Follicular B helper T cells</span>

Follicular helper T cells (also known as follicular B helper T cells and abbreviated as TFH), are antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches, and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5. Upon cellular interaction and cross-signaling with their cognate follicular (Fo B) B cells, TFH cells trigger the formation and maintenance of germinal centers through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4. TFH cells also migrate from T cell zones into these seeded germinal centers, predominantly composed of rapidly dividing B cells mutating their Ig genes. Within germinal centers, TFH cells play a critical role in mediating the selection and survival of B cells that go on to differentiate either into long-lived plasma cells capable of producing high affinity antibodies against foreign antigen, or germinal center-dependent memory B cells capable of quick immune re-activation in the future if ever the same antigen is re-encountered. TFH cells are also thought to facilitate negative selection of potentially autoimmune-causing mutated B cells in the germinal center. However, the biomechanisms by which TFH cells mediate germinal center tolerance are yet to be fully understood.

Natural killer T (NKT) cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self and foreign lipids and glycolipids. They constitute only approximately 1% of all peripheral blood T cells. Natural killer T cells should neither be confused with natural killer cells nor killer T cells.

Mucosal-associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.

Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity.

Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to self antigens implicated in autoimmune diseases. It must provide absence of specific antibodies for exactly that antigenes.

References

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  2. ↑ 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.
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  4. 1 2 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.
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  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
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