The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality

Li, Chaofan; Zhu, Bibo; Son, Young Min; Wang, Zheng; Jiang, Li; Xiang, Min; Ye, Zhenqing; Beckermann, Kathryn E.; Wu, Yue; Jenkins, James W.; Siska, Peter J.; Vincent, Benjamin G.; Prakash, Y. S.; Peikert, Tobias; Edelson, Brian T.; Taneja, Reshma; Kaplan, Mark H.; Rathmell, Jeffrey C.; Dong, Haidong; Hitosugi, Taro; Sun, Jie

doi:10.1016/j.immuni.2019.08.013

Cited by 162 publications

(181 citation statements)

References 77 publications

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“…5 f, g). These data suggest that Bhlhe40 is required for the establishment of the overall lung-resident CD4 + T cell population following influenza infection, as was observed with the lung-resident CD8 + T cells 55 . As the result, the magnitude of both T RH and non-T RH cells in the lungs were significantly decreased (Fig.…”

Section: Resultssupporting

confidence: 63%

“…Since lung T RH and non-T RH cells expressed high levels of Bhlhe40 relative to splenic T FH cells (Fig 4a), we investigated the roles of Bhlhe40 in lung T RH responses relative to splenic T FH cells. Consistent with high Bhlhe40 expression in T RH cells, lung T RH cells were enriched with Bhlhe40-associated genes 55 compared to splenic T FH cells (Fig. 6f).…”

Section: Resultssupporting

confidence: 60%

“…6g-i and Extended 5 d, e). Previously, we have reported that Bhlhe40 is required for the survival CD8 + T cells in non-lymphoid tissues 55 . Consistent with that observation, Bhlhe40 deficiency resulted in enhanced cellular apoptosis in both lung T RH and non-T RH cells (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…We have demonstrated before that Bhlhe40 is critical for the development of tissue-resident CD8 + T cell responses 55 . Since lung T RH and non-T RH cells expressed high levels of Bhlhe40 relative to splenic T FH cells (Fig 4a), we investigated the roles of Bhlhe40 in lung T RH responses relative to splenic T FH cells.…”

Section: Resultsmentioning

confidence: 99%

“…When compared to splenic T FH cells, lung CD4 + PD-1 Hi FR4 Hi cells showed increased expression of genes associated with tissue migration, retention and function including Ccr2, Bhlhe40 and Cxcr6 (Fig. 3e) 54, 55 . GSEA analysis revealed that lung CD4 + PD-1 Hi FR4 Hi had significant enrichment of T RM -associated genes relative to splenic T FH cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

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Cheon

et al. 2020

Preprint

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32The roles of CD4 + T helper cells (TH) in shaping localized memory B and CD8 + T cell immunity 33 in the mucosal tissues are largely unexplored. Here, we report that lung TH cells provide local 34 assistance for the optimal development of tissue-resident memory B (BRM) and CD8 + T (TRM) 35 cells following the resolution of primary influenza virus infection. We identify a population of 36 tissue-resident CD4 + TH (aka TRH) cells that co-exhibit follicular T helper (TFH) and TRM cell 37 features and mediate local help of CD4 + T cells to B and CD8 + T cells. Optimal TRH cell 38 formation requires lung B cells and transcription factors involved in TFH or TRM development. 39Further, we show that TRH cells deliver local help to B and CD8 T cells through CD40L and IL-40 21-dependent mechanisms. Our data have uncovered a new tissue-resident TH cell population 41 that is specialized in assisting the development of mucosal protective B and CD8 + T cell 42 responses in situ.

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Section: Resultssupporting

confidence: 63%

Section: Resultssupporting

confidence: 60%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Son

Cheon

et al. 2020

Preprint

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Emerging Epigenetic‐Based Nanotechnology for Cancer Therapy: Modulating the Tumor Microenvironment

Zhang

Huang

et al. 2023

Advanced Science

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Dysregulated epigenetic modifications dynamically drive the abnormal transcription process to affect the tumor microenvironment; thus, promoting cancer progression, drug resistance, and metastasis. Nowadays, therapies targeting epigenetic dysregulation of tumor cells and immune cells in the tumor microenvironment appear to be promising adjuncts to other cancer therapies. However, the clinical results of combination therapies containing epigenetic agents are disappointing due to systemic toxicities and limited curative effects. Here, the role of epigenetic processes, including DNA methylation, post‐translational modification of histones, and noncoding RNAs is discussed, followed by detailed descriptions of epigenetic regulation of the tumor microenvironment, as well as the application of epigenetic modulators in antitumor therapy, with an emphasis on the epigenetic‐based advanced drug delivery system in targeting the tumor microenvironment.

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ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism

Tan

Zhao

et al. 2023

Advanced Science

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Extracellular regulated protein kinases (ERK) signaling is a master regulator of cell behavior, life, and fate. Although ERK pathway is shown to be involved in T‐cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signaling pathway is activated in allograft‐infiltrating T cells. On the basis of surface plasmon resonance technology, lycorine is identified as an ERK‐specific inhibitor. ERK inhibition by lycorine significantly prolongs allograft survival in a stringent mouse cardiac allotransplant model. As compared to untreated mice, lycorine‐treated mice show a decrease in the number and activation of allograft‐infiltrated T cells. It is further confirmed that lycorine‐treated mouse and human T cells are less responsive to stimulation in vitro, as indicated by their low proliferative rates and decreased cytokine production. Mechanistic studies reveal that T cells treated with lycorine exhibit mitochondrial dysfunction, resulting in metabolic reprogramming upon stimulation. Transcriptome analysis of lycorine‐treated T cells reveals an enrichment in a series of downregulated terms related to immune response, the mitogen‐activated protein kinase cascade, and metabolic processes. These findings offer new insights into the development of immunosuppressive agents by targeting the ERK pathway involved in T‐cell activation and allograft rejection.

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The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality

Cited by 162 publications

References 77 publications

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Emerging Epigenetic‐Based Nanotechnology for Cancer Therapy: Modulating the Tumor Microenvironment

ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism

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The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality

Cited by 162 publications

References 77 publications

Tissue-resident CD4+T helper cells assist protective respiratory mucosal B and CD8+T cell memory responses

Tissue-resident CD4+T helper cells assist protective respiratory mucosal B and CD8+T cell memory responses

Emerging Epigenetic‐Based Nanotechnology for Cancer Therapy: Modulating the Tumor Microenvironment

ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism

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Product

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Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses