B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell-dominant T-cell responses via IL-33

Blood Advances
Hiroshi ArimaAkifumi Takaori-Kondo

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

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Citations

May 21, 2019·Arthritis & Rheumatology·Dallas M RohraffAmr H Sawalha
Jul 28, 2019·Journal of Immunology Research·Georgia TsaouliMaria Pia Felli
Oct 28, 2019·International Journal of Molecular Sciences·Alessandro AllegraSebastiano Gangemi
Aug 9, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Matthew T StierR Stokes Peebles
Jul 17, 2019·Molecular Cancer Research : MCR·Zhaoji PanGuoping Niu
Dec 31, 2020·Cells·Laura GragnaniAnna Linda Zignego
Feb 23, 2021·Frontiers in Immunology·Matthew Garis, Lee Ann Garrett-Sinha

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