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Cathepsin W restrains peripheral regulatory T cells for mucosal immune quiescence.

ABSTRACT: Peripheral regulatory T (pT_reg) cells are a key T cell lineage for mucosal immune tolerance and anti-inflammatory responses, and interleukin-2 receptor (IL-2R) signaling is critical for T_reg cell generation, expansion, and maintenance. The expression of IL-2R on pT_reg cells is tightly regulated to ensure proper induction and function of pT_reg cells without a clear molecular mechanism. We here demonstrate that Cathepsin W (CTSW), a cysteine proteinase highly induced in pT_reg cells under transforming growth factor-β stimulation is essential for the restraint of pT_reg cell differentiation in an intrinsic manner. Loss of CTSW results in elevated pT_reg cell generation, protecting the animals from intestinal inflammation. Mechanistically, CTSW inhibits IL-2R signaling in pT_reg cells by cytosolic interaction with and process of CD25, repressing signal transducer and activator of transcription 5 activation to restrain pT_reg cell generation and maintenance. Hence, our data indicate that CTSW acts as a gatekeeper to calibrate pT_reg cell differentiation and function for mucosal immune quiescence.

SUBMITTER: Li J

PROVIDER: S-EPMC10337914 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Cathepsin W restrains peripheral regulatory T cells for mucosal immune quiescence.

Li Jian J Chen Zuojia Z Kim Girak G Luo Jialie J Hori Shohei S Wu Chuan C

Science advances 20230712 28

Peripheral regulatory T (pTreg) cells are a key T cell lineage for mucosal immune tolerance and anti-inflammatory responses, and interleukin-2 receptor (IL-2R) signaling is critical for Treg cell generation, expansion, and maintenance. The expression of IL-2R on pTreg cells is tightly regulated to ensure proper induction and function of pTreg cells without a clear molecular mechanism. We here demonstrate that Cathepsin W (CTSW), a cysteine proteinase h ...[more]

PMID: 37436991

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Project description:BackgroundRegulatory immune cells may modulate the lymphoma microenvironment and are of great interest due to the increasing prevalence of treatment with immunotherapies in lymphoma patients. The aim was to explore the composition of different immune regulatory cell subsets in the peripheral blood of newly diagnosed lymphoma patients in relation to treatment outcome.MethodsForty-three newly diagnosed patients with lymphoma were included in the study; 24 with high-grade B-cell lymphoma (HGBCL) and 19 with classical Hodgkin lymphoma (cHL). Peripheral blood was prospectively collected and immune regulatory cells were identified by multi-color flow cytometry and analyzed in relation to healthy blood donors and clinical characteristics and outcome.ResultsThe percentage of CD3-positive T-cells was lower (p = 0.03) in the peripheral blood of lymphoma patients at diagnosis compared to healthy blood donors regardless of lymphoma subtype, although statistically, neither the percentage of monocytes (p = 0.2) nor the T-cell/monocyte ratio (p = 0.055) differed significantly. A significant decrease in the percentage of a subset of regulatory NK cells (CD7+/CD3-/CD56bright/CD16dim/-) was identified in the peripheral blood of lymphoma patients compared to healthy blood donors (p = 0.003). Lymphoma patients also had more granulocytic myeloid-derived suppressor cells (MDSCs) (p = 0.003) compared to healthy blood donors, whereas monocytic MDSCs did not differ significantly (p = 0.07). A superior disease-free survival was observed for cHL patients who had an increase in the percentage of granulocytic MDSCs (p = 0.04).ConclusionsAn altered profile of immune cells in the peripheral blood with a decrease in T-cells and regulatory NK-cells was observed in newly diagnosed lymphoma patients. CHL patients with higher percentages of regulatory NK cells and higher percentages of granulocytic MDSCs might have a better outcome, although the number of patients was low.

Dataset Information

Cathepsin W restrains peripheral regulatory T cells for mucosal immune quiescence.

Publications

Cathepsin W restrains peripheral regulatory T cells for mucosal immune quiescence.

Similar Datasets

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