CD5 Promotes IL-10 Production in Chronic Lymphocytic Leukemia B Cells through STAT3 and NFAT2 Activation

Garaud, Soizic; Morva, Ahsen; Lemoine, Sébastien; Hillion, Sophie; Bordron, Anne; Pers, Jacques‐Olivier; Berthou, Christian; Mageed, Rizgar A.; Renaudineau, Yves; Youinou, Pierre

doi:10.4049/jimmunol.1003050

Cited by 66 publications

(67 citation statements)

References 50 publications

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“…Similar pattern of survival and apoptosis responses following anti-CD5 stimulation were obtained in the study of PerezChacon and collaborators (Perez-Chacon et al, 2007). Moreover, authors showed that in unstimulated and resting CD5 transfected B cells, it was observed that CD5 + B cells produce more IL-10 than CD5 -B cells enhancing survival of B cells , Garaud et al, 2011.…”

Section: Calcium Signaling and Chronic Lymphocytic Leukemia 383supporting

confidence: 63%

Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

Debant

Hémon²,

Brigaudeau³

et al. 2015

Int. J. Dev. Biol.

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Ca2+ signaling is a key regulator of B lymphocyte cell fate and defects in this signaling pathway have been reported in numerous diseases such as Chronic lymphocytic leukemia (CLL). CLL is a B cell clonal disorder characterized by the accumulation of mature monoclonal CD5 + B cells. Although CLL could be considered to be a proliferative disease, most circulating CLL B cells are arrested in the G0 phase of the cell cycle and present both defects in calcium (Ca 2+ ) homeostasis and signaling. The Ca 2+ response to antigen ligation is heterogeneous and related, in part, to defects arising from the incapacity to respond to B cell receptor (BCR) engagement (anergy), to the expression of T cell kinases (e.g. Zap70), and to the presence of negative feedback regulation by phosphatases (e.g. SHP-1). Anergic CD5 + CLL B cells are characterized by an elevated basal Ca 2+ level, IgM/CD79 downregulation, a constitutive activation of BCR pathway kinases, and an activation of the nuclear factor of activated T cells (NF-AT). Based on the Ca2+ response, patients are classified into three groups: unresponders, responders with apoptosis, and responders with entry in the cell cycle. Moreover, internal and direct interaction between leukemic BCR-HCDR3 epitopes at the plasma membrane and interaction between Bcl-2 and the IP3-receptor at the endoplasmic reticulum are also suspected to interfere with the intracellular Ca 2+ homeostasis in CLL-B cells. As a whole, the Ca 2+ pathway is emerging to play a key role in malignant CLL-B survival, disease progression, and last but not least, in the therapeutic response.

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Section: Calcium Signaling and Chronic Lymphocytic Leukemia 383supporting

confidence: 63%

Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

Debant

Hémon²,

Brigaudeau³

et al. 2015

Int. J. Dev. Biol.

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“…We propose that the CD5 marker is an acceptable measure of Breg cells based on our data demonstrating a high correlation with CD24 hi CD38 hi and IgM + CD5 + subpopulations. CD5 is reported to induce IL-10 expression and promote cell survival in human B cells (27), human chronic lymphocytic leukemia B cells (28), and mice (29). In mice, CD5 + CD1d + B cells secrete IL-10 and have a regulatory function evidenced by their inhibition of INF-g and TNF-a expression in T cells (30).…”

Section: Discussionmentioning

confidence: 99%

Decreased CD5+ B Cells in Active ANCA Vasculitis and Relapse after Rituximab

Bunch¹,

G.²,

Khandoobhai³

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives B cell significance in ANCA disease pathogenesis is underscored by the finding that ANCA alone can cause disease in mouse models and by the effectiveness of rituximab as therapy in ANCA-small vessel vasculitis (ANCA-SVV). To avoid infections and adverse events from therapy, clinicians require improved markers of disease activity and impending relapse to guide immunosuppression strategies after rituximab treatment.Design, setting, participants, & measurements The B cell phenotype was investigated in patients with active ANCA-SVV and in remission. From 2003 to 2009, 54 patients were followed longitudinally for 4-99 months and compared with 68 healthy controls. In a subset of 19 patients, the B cell immunophenotype was examined in samples after rituximab therapy.Results Patients with active ANCA-SVV had lower %CD5 + B cells, whereas %CD5 + B cells from patients in remission were indistinguishable from healthy controls. After rituximab, median time to relapse was 31 months in patients maintaining normalized %CD5 + B cells, with or without maintenance immunosuppression. Among patients whose B cells repopulated with low %CD5 + B cells or had a sharply declining %CD5 + B cells, those who were on low or no maintenance immunosuppression relapsed sooner (median 17 months) than patients who were maintained on high levels of oral maintenance immunosuppression (29 months; P=0.002). Conclusions The %CD5+ B cells, as a component of the human B regulatory cell phenotype, is a useful indicator of disease activity, remission, and future relapse, and thus may guide remission maintenance therapy after rituximab treatment.

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“…CD5-positive CLL B cells also proliferate in response to CpG, however, to a lesser extent (Figure 3 3.3. CpG stimulation leads to IL-10 production CLL B cells are known to secrete high amounts of the anti-inflammatory cytokine IL-10, mainly due to their elevated CD5 expression [17]. To test whether there is a difference between the CD5-negative and CD5-positive B cells of the patients regarding this ability, IL-10 production was measured from cell culture supernatants after stimulation with anti-BCR, CpG and their combination.…”

Section: Proliferation Of Cll B Cellsmentioning

confidence: 99%

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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CD5 Promotes IL-10 Production in Chronic Lymphocytic Leukemia B Cells through STAT3 and NFAT2 Activation

Cited by 66 publications

References 50 publications

Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

Decreased CD5+ B Cells in Active ANCA Vasculitis and Relapse after Rituximab

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

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