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

Abstract

B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 containing the known exon 1 (E1A) and other CD5 transcripts containing the new exon 1 (E1B). These malignant B cells, as well as B cell lines transfected with cDNA for E1A-cd5 or with cDNA for E1B-cd5 produce IL-10, raising the possibility that CD5 participates in the secretion of IL-10. We identified transcription factors involved in this production in CD5+ B lymphocytes from CLL patients and in E1A-cd5–transfected or E1B-cd5–transfected Jok cells. STAT3 is activated via phosphorylation of serine 727 but also NFAT2 through its translocation into the nucleus. Chromatin immunoprecipitation experiments confirmed the role of STAT3 and allowed the discovery of a role for NFAT2 in IL-10 production. Both transcription factors bind not only to the enhancer of the Il-10 gene but also to the promoter of the Il-5 and Il-13 genes. Furthermore, transfection of B cell lines with E1A-cd5 or E1B-cd5 established that activation of STAT3 and NFAT2 is regulated by CD5. The same holds true for the production of IL-10, IL-5, and IL-13 and the expression of the receptors for these cytokines. This interpretation was confirmed by two experiments. In the first, downregulation of CD5 by small interfering RNAs lowered the production of IL-10. In the second experiment, transfection of the GFP-NFAT2 gene into B lymphocytes induced nuclear translocation of NFAT2 in CD5+ but not in CD5− B cells. Thus, CD5 expression is associated with NFAT2 activity (and mildly STAT3 activity), indicating that CD5 controls IL-10 secretion.

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

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

“…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).…”

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

“…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.…”