B10 cell

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]

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 CD1d^hiCD5⁺ 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]