Role of B cell receptor signaling in IL‐10 production by normal and malignant B‐1 cells

Alhakeem, Sara S.; Sindhava, Vishal; McKenna, Mary K.; Gachuki, Beth W.; Byrd, John C.; Muthusamy, Natarajan; Bondada, Subbarao

doi:10.1111/nyas.12802

Cited by 34 publications

(46 citation statements)

References 47 publications

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“…In contrast to this, B cells of CLL patients possess the capacity to secrete substantial amounts of IL-10 that can promote leukemic cell survival via immunosuppression [25,27]. In agreement with these data, we found a much higher -up to ten-fold -amount of IL-10 in the supernatant of stimulated B-CLL cells than in the case of healthy controls.…”

Section: Discussionsupporting

confidence: 88%

Functional studies of chronic lymphocytic leukemia B cells expressing β 2 -integrin type complement receptors CR3 and CR4

et al. 2017

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The expression and role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in B cellsare not yet explored in contrast to myeloid cells, where these β 2 -integrin type receptors are known to participate in various cellular functions, including phagocytosis, adherence and migration. Here we aimed to reveal the expression and role of CR3 and CR4 in human B cells. In B cells of healthy donors CR3 and CR4 are scarcely expressed. However, two patients with chronic lymphocytic leukemia (CLL) characterized by a peculiar immunephenotype containing both CD5-positive and CD5-negative B cell populations made possible to study these molecules in distinct B cell subsets. We found that CD11b and CD11c were expressed on both CD5-positive and CD5-negative B cells, albeit to different extents. Our data suggest that these receptors are involved in spreading, since this activity of CpGactivated B cells on fibrinogen could be partially blocked by monoclonal antibodies specific for CD11b or CD11c. CpG-stimulation lead to proliferation of both CD5-positive and CD5-negative B cells of the patients with a less pronounced effect on the CD5-positive cells. In contrast to normal B cells, CLL B cells of both patients reacted to CpG-stimulation with robust IL-10 production. The concomitant, suboptimal stimulus via the BCR and TLR9 exerted either a synergistic enhancing effect or resulted in inhibition of proliferation and IL-10 production of patients' B cells.Our data obtained studying B cells of leukemic patients point to the role of CR3 in the interaction of tumor cells with the microenvironment and suggest the involvement of IL-10 producing B cells in the pathologic process.

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Section: Discussionsupporting

confidence: 88%

Functional studies of chronic lymphocytic leukemia B cells expressing β 2 -integrin type complement receptors CR3 and CR4

et al. 2017

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“…In this way, these cells have an important role in maintaining tissue homeostasis, and innate‐like immune defence against mucosal pathogens 32 , 33 . In addition, B‐1 cells produce interleukin‐10 and have important roles in the maintenance of self‐tolerance by the uptake and presentation of endogenous antigens 34 , 35 . B‐1 cells have also been linked to autoimmunity in both human patients and murine models of disease 36 .…”

Section: Discussionmentioning

confidence: 99%

Murine LRBA deficiency causes CTLA‐4 deficiency in Tregs without progression to immune dysregulation

et al. 2017

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Inherited mutations in lipopolysaccharide-responsive beige-like anchor (LRBA) cause a recessive human immune dysregulation syndrome with memory B-cell and antibody deficiency (common variable immunodeficiency), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated T cells and multiple autoimmune diseases. To understand the pathogenesis of the syndrome, C57BL/6 mice carrying a homozygous truncating mutation in Lrba were produced using CRISPR/Cas9-mediated gene targeting. These mice revealed that LRBA has a critical, cell-autonomous role in promoting cytotoxic T-lymphocyte antigen-4 (CTLA-4) accumulation within CD4 effector T cells and FOXP3+ T-regulatory cells (Tregs). In young mice, or in chimeric mice where only half of the T cells are LRBA deficient, low CTLA-4 was the only detectable abnormality in Tregs, whereas in old mice FOXP3 was also decreased. Low CTLA-4 did not translate into increased CD86 on B cells unless the LRBA-deficient mice were immunised, and neither immunisation nor chronic lymphocytic choriomeningitis virus infection precipitated immune dysregulation. LRBA deficiency did not alter antigen-specific B-cell activation, germinal centre (GC) formation, isotype switching or affinity maturation. Paradoxically, CD86 was decreased on GC B cells in LRBA-deficient mice, pointing to compensatory mechanisms for controlling CD86 in the face of low CTLA-4. These results add to the experimental rationale for treating LRBA deficiency with the CTLA4-Ig fusion protein, Abatacept, and pose questions about the limitations of laboratory experiments in mice to reproduce human disease in natura.

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“…B1 cells are known to differ from B2 cells in their failure to proliferate in response to BCR ligation, which is postulated to reflect increased phosphatase activity and IL10 production [15, 46–49]. Unlike B2 cells, B1 cells had a measurable LPS response prior to IL10 neutralization.…”

Section: Discussionmentioning

confidence: 99%

Macrophage regulation of B cell proliferation

Goldman

Valiuskyte

Londregan

et al. 2017

Cellular Immunology

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Unlike organized lymphoid tissue, the tumor microenvironment (TME) often includes a high proportion of immunosuppressive macrophages. We model the TME by culturing peritoneal cavity (PerC) cells that naturally have a high macrophage to lymphocyte ratio. Prior studies revealed that, following TCR ligation, PerC T cell proliferation is suppressed due to IFNγ-triggered inducible nitric oxide synthase expression. In this study we assessed the ability of PerC B cells to respond to surrogate activating signals in the presence of high numbers of macrophages. Surface IgM (BCR) ligation led to cyclooxygenase-mediated, and TLR-4 ligation to IL10-mediated, suppression of PerC B cell proliferation. In contrast, PerC B cells had a robust response to CD40 ligation, which could overcome the suppression generated by the BCR or TLR-4 response. However, the CD40 response was suppressed by concurrent TCR ligation. These results reveal the challenges of promoting B and T cell responses in macrophage-rich conditions that model the TME.

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Role of B cell receptor signaling in IL‐10 production by normal and malignant B‐1 cells

Cited by 34 publications

References 47 publications

Functional studies of chronic lymphocytic leukemia B cells expressing β 2 -integrin type complement receptors CR3 and CR4

Functional studies of chronic lymphocytic leukemia B cells expressing β 2 -integrin type complement receptors CR3 and CR4

Murine LRBA deficiency causes CTLA‐4 deficiency in Tregs without progression to immune dysregulation

Macrophage regulation of B cell proliferation

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