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 CD81 T cells. The mice were susceptible to soft tissue sarcoma and defective production of CD81 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 (DLBCL) samples showed that an activated Notch-signaling signature correlates positively with IL33 expression and Treg cell-rich gene-expression signatures. These findings indicate that B cells harboring dysregulated Notch signaling alter T-cell responses via IL-33, and suggest that aberrant activation of Notch signaling plays a role in fostering immune privilege in mature B-cell neoplasms.