B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell-dominant T-cell responses via IL-33
Abstract
The Notch-signaling pathway in a variety of mature B-cell neoplasms is often activated by gene alterations, but its role remains unclear. Here, we show that B cells harboring dysregulated activation of Notch1 signaling have an immunomodulatory effect on T cells by amplifying regulatory T (Treg) and T helper 2 (Th2) cell responses in an interleukin-33 (IL-33)-dependent manner. A conditional mouse model, in which constitutive expression of an active form of Notch1 is induced in B cells by Aicda gene promoter-driven Cre recombinase, revealed no obvious phenotypic changes in B cells; however, mice demonstrated an expansion of Treg and Th2 cell subsets and a decrease in cytokine production by Th1 and CD8+ T cells. The mice were susceptible to soft tissue sarcoma and defective production of CD8+ T cells specific for inoculated tumor cells, suggesting impaired antitumor T-cell activity. Gene-expression microarray revealed that altered T-cell responses were due to increased IL-33 production by Notch1-activated B cells. Knockout of IL33 or blockade of IL-33 by a receptor-blocking antibody abrogated the Treg and Th2 cell-dominant T-cell response triggered by B cells. Gene-expression data derived from human diffuse large B-cell lymphoma (...Continue Reading
References
Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover
Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse
Notch ligands expressed by follicular dendritic cells protect germinal center B cells from apoptosis
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