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Ddb1 Is Essential for the Expansion of CD4⁺ Helper T Cells by Regulating Cell Cycle Progression and Cell Death.

ABSTRACT: Follicular helper T (T_FH) cells are specialized CD4⁺ helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of T_FH cells is incompletely understood. Here, we reported that Damage-specific DNA binding protein 1 (Ddb1) was required for expansion of CD4⁺ helper T cells including T_FH and Th1 cells, germinal center response, and antibody response to acute viral infection. Ddb1 deficiency in activated CD4⁺ T cells resulted in cell cycle arrest at G2-M phase and increased cell death, due to accumulation of DNA damage and hyperactivation of ATM/ATR-Chk1 signaling. Moreover, mice with deletion of both Cul4a and Cul4b in activated CD4⁺ T cells phenocopied Ddb1-deficient mice, suggesting that E3 ligase-dependent function of Ddb1 was crucial for genome maintenance and helper T-cell generation. Therefore, our results indicate that Ddb1 is an essential positive regulator in the expansion of CD4⁺ helper T cells.

SUBMITTER: Yang L

PROVIDER: S-EPMC8435776 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Ddb1 Is Essential for the Expansion of CD4+ Helper T Cells by Regulating Cell Cycle Progression and Cell Death.

Yang Lingtao L Chen Wei W Li Li L Xiao Yueyue Y Fan Shilin S Zhang Quan Q Xia Tian T Li Mengjie M Hong Yazhen Y Zhao Tongjin T Li Qiyuan Q Liu Wen-Hsien WH Xiao Nengming N

Frontiers in immunology 20210830

Follicular helper T (TFH) cells are specialized CD4+ helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of TFH cells is incompletely understood. Here, we reported that Damage-specific DNA binding protein 1 (Ddb1) was required for expansion of CD4+ helper T cells including TFH and Th1 cells, germinal center response, and antibody response to acute viral infection. Ddb1</i ...[more]

PMID: 34526995

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Project description:BackgroundAging is the most important risk factor for prostate cancer (PCa), but how age contributes to PCa is poorly understood. Aging is characterized by low-grade systemic inflammation (i.e., inflammaging) that is often attributed to the progressive activation of immune cells over time, which may play an important role in prostate carcinogenesis. Th17 response is elevated in aging humans and mice, but it remains unknown whether it is increased in prostate tissue or contributes to prostate carcinogenesis during aging. In this study, we aimed to determine the role of age-related Th17 response in PCa cell growth, migration, and invasion.MethodsC57BL/6J (B6) mouse was used as an aging animal model and the prostate histopathology during aging was analyzed. Splenic CD4+ T cells were isolated from young (16-20 weeks old) and aged (96-104 weeks old) mice, and cultured in the presence of plate-bound anti-CD3/anti-CD28, with or without Th17 differentiation conditions. The cells were collected and used for subsequent flow cytometry or quantitative reverse transcription polymerase chain reaction. The supernatant was collected and used to treat PCa cell lines. The treated PCa cells were analyzed for cell viability, migration, invasion, and nuclear factor kappa B (NF-κB) signaling.ResultsAged mice had enlarged prostate glands and increased morphological alterations, with not only increased inflammatory cell infiltration but also increased Th17 cytokines in prostate tissue, compared to young mice. Naïve CD4+ T cells from aged mice differentiated increased interleukin (IL)-17-expressing cells. CD4+ T cells from aged mice spleen had increased Th17 cells, Th17 cytokines and Th17/Treg ratio compared to young mice. Factors secreted from aged CD4+ T cells, especially from ex vivo differentiated Th17 cells, not only promoted PCa cell viability, migration, and invasion but also activated the NF-κB signaling in PCa cells compared to young mice.ConclusionsThese results indicate that age-related CD4+ T cells, especially Th17 cells-secreted factors have the potential to contribute to prostate carcinogenesis. Our work could prompt further research using autochthonous PCa mouse models at different ages to elucidate the functional role of Th17 response in prostate carcinogenesis during aging.

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Ddb1 Is Essential for the Expansion of CD4⁺ Helper T Cells by Regulating Cell Cycle Progression and Cell Death.

Publications

Ddb1 Is Essential for the Expansion of CD4<sup>+</sup> Helper T Cells by Regulating Cell Cycle Progression and Cell Death.

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