Themis suppresses the effector function of CD8+ T cells in acute viral infection

Tang, Jian; Jia, Xian; Li, Jian; Dong, Junchen; Wang, Jiayu; Li, Wanyun; Zhu, Y.; Hu, Yawen; Hou, Bowen; Lin, Chunjie; Yu, Cong; Ren, Tong; Yan, Changsheng; Yang, Heng; Lai, Qian; Zheng, Haiping; Bao, Yiliang; Gautam, Namrata; Wang, Hong-Rui; Xu, Bing; Chen, Xiao Lei; Li, Qing; Gascoigne, Nicholas R J; Fu, Guo

doi:10.1038/s41423-023-00997-z

Cited by 6 publications

(6 citation statements)

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“…The acute deletion model allowed us to identify critical functions for Themis in peripheral T cell activation and signaling, which were not found in the dLck-Cre Themis deletion model (leading to absence of Themis in T cells from the SP thymocyte stage onwards) (Brzostek et al, 2020). In the dLck-Cre-mediated cKO model in OT-I mice, we found negligible reduction in TCR stimulation with OVA APLs but altered memory versus effector cell differentiation in responses to acute viral infection (Brzostek et al, 2020;Tang et al, 2023). Because of the possibility that the T cells could change their sensitivity to stimulation (Grossman & Paul, 1992) over their lifespan after passing the SP thymocyte stage, this suggests that the cells had adapted their signaling functions to overcome a Themis defect.…”

Section: Discussionmentioning

confidence: 85%

“…Here, from the 3D co-culture of B16 melanoma cells and CTL from Themis cWT or Themis cKO OT-I mice treated with TX, we found that Themis-deficient CTL showed significantly reduced cytotoxic ability despite their significantly increased migration towards the target tumor cells. This could be related to Themis’ (with Shp1) interaction with CD137 which reduces signaling through CD137-containing chimeric antigen receptors (CARs) ( Sun et al, 2020 ), or to its effect on PD-1 activity through Shp1 or Shp2 ( Kinosada et al, 2017 ; Tang et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, peripheral Themis deficiency in CD4 + T cells has disparate effects on activation of naïve as compared with differentiated Th1 CD4 + T cells ( Yang et al, 2022a ). In addition, in response to an acute viral infection, Themis deficiency increased CD8 + T cell differentiation into short-lived effector cells, but inhibited differentiation into memory cells ( Tang et al, 2023 ). These differences could result from the different roles of Themis in regulation of subset-specific, TCR-dependent, and TCR-independent signals, but may also reflect adaptation to Themis deficiency during CD4 + differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Themis controls T cell activation, effector functions, and metabolism of peripheral CD8⁺T cells

Gautam,

Wojciech,

Yap

et al. 2023

Life Sci. Alliance

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Themis is important in regulating positive selection of thymocytes during T cell development, but its role in peripheral T cells is less understood. Here, we investigated T cell activation and its sequelae using a tamoxifen-mediated, acute Themis deletion mouse model. We find that proliferation, effector functions including anti-tumor killing, and up-regulation of energy metabolism are severely compromised. This study reveals the phenomenon of peripheral adaptation to loss of Themis, by demonstrating direct TCR-induced defects after acute deletion of Themis that were not evident in peripheral T cells chronically deprived of Themis in dLck-Cre deletion model. Peripheral adaptation to long-term loss was compared using chronic versus acute tamoxifen-mediated deletion and with the (chronic) dLck-Cre deletion model. We found that upon chronic tamoxifen-mediated Themis deletion, there was modulation in the gene expression profile for both TCR and cytokine signaling pathways. This profile overlapped with (chronic) dLck-Cre deletion model. Hence, we found that peripheral adaptation induced changes to both TCR and cytokine signaling modules. Our data highlight the importance of Themis in the activation of CD8+T cells.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Themis controls T cell activation, effector functions, and metabolism of peripheral CD8⁺T cells

Gautam,

Wojciech,

Yap

et al. 2023

Life Sci. Alliance

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“…We observed that clonally expanded GZMB+ cytotoxic T cells from non-progressors showed higher expression levels of genes related to cytotoxicity and activation, such as TYROBP , CXCR4 , and members of the AP-1 pathway, compared to progressors (Figure 7K) . Clonally expanded GZMB+ cytotoxic T cells from progressors showed higher levels of GIMAP genes, which may be associated with increased apoptosis 30 , and THEMIS , which can suppress cytotoxic responses 31 , however higher levels of maturation markers ITGB1 and CX3CR1 were also observed, suggesting that the functionality of clonally expanded GZMB+ cytotoxic T cells may be more nuanced.…”

Section: Resultsmentioning

confidence: 99%

Long-Term Follow-Up Defines the Population That Benefits from Early Interception in a High-Risk Smoldering Multiple Myeloma Clinical Trial Using the Combination of Ixazomib, Lenalidomide, and Dexamethasone

Nadeem,

Aranha,

Redd

et al. 2024

Preprint

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Background: Early therapeutic intervention in high–risk SMM (HR–SMM) has demonstrated benefit in previous studies of lenalidomide with or without dexamethasone. Triplets and quadruplet studies have been examined in this same population. However, to date, none of these studies examined the impact of depth of response on long–term outcomes of participants treated with lenalidomide–based therapy, and whether the use of the 20/2/20 model or the addition of genomic alterations can further define the population that would benefit the most from early therapeutic intervention. Here, we present the results of the phase II study of the combination of ixazomib, lenalidomide, and dexamethasone in patients with HR–SMM with long-term follow–up and baseline single-cell tumor and immune sequencing that help refine the population to be treated for early intervention studies. Methods: This is a phase II trial of ixazomib, lenalidomide, and dexamethasone (IRD) in HR–SMM. Patients received 9 cycles of induction therapy with ixazomib 4mg on days 1, 8, and 15; lenalidomide 25mg on days 1 to 21; and dexamethasone 40mg on days 1, 8, 15, and 22. The induction phase was followed by maintenance with ixazomib 4mg on days 1, 8, and 15; and lenalidomide 15mg d1 to 21 for 15 cycles for 24 months of treatment. The primary endpoint was progression–free survival after 2 years of therapy. Secondary endpoints included depth of response, biochemical progression, and correlative studies included single–cell RNA sequencing and/or whole–genome sequencing of the tumor and single-cell sequencing of immune cells at baseline. Results: Fifty–five patients, with a median age of 64, were enrolled in the study. The overall response rate was 93%, with 31% of patients achieving a complete response (CR) and 45% achieving a very good partial response (VGPR) or better. All patients that achieved a CR sustained it for greater than 6 months. The most common grade 3 or greater treatment-related hematologic toxicities were neutropenia (16 patients; 29%), leukopenia (10 patients; 18%), lymphocytopenia (8 patients; 15%), and thrombocytopenia (4 patients; 7%). Non-hematologic grade 3 or greater toxicities included hypophosphatemia (7 patients; 13%), rash (5 patients; 9%), and hypokalemia (4 patients; 7%). After a median follow–up of 50 months, the median progression–free survival (PFS) was 48.6 months (95% CI: 39.9 – not reached; NR) and median overall survival has not been reached. The median progression–free survival in the sustained CR group was not reached, compared to 38 months in the non–CR group (p = 0.0018). Similarly, patients achieving VGPR or better had a significantly better progression-free survival (p<0.001) compared to those who did not achieve VGPR (median PFS 58.2 months vs. 31.3 months). Biochemical progression preceded or was concurrent with the development of SLiM–CRAB criteria in eight patients during follow–up, indicating that biochemical progression is a meaningful endpoint that correlates with the development of end–organ damage. High–risk 20/2/20 participants had the worst PFS compared to low- and intermediate–risk participants. The use of whole genome or single–cell sequencing of tumor cells identified high–risk aberrations that were not identified by FISH alone and aided in the identification of participants at risk of progression. scRNA–seq analysis revealed a positive correlation between MHC class I expression and response to proteasome inhibition and at the same time a decreased proportion of GZMB+ T cells within the clonally expanded CD8+ T cell population correlated with suboptimal response. Conclusions: Ixazomib, lenalidomide, and dexamethasone in HR-SMM demonstrates significant clinical activity with an overall favorable safety profile. Achievement of sustained CR and VGPR or greater led to significant improvement in time to progression, suggesting that achieving deep response is beneficial in HR–SMM. Biochemical progression correlates with end-organ damage. Patients with high–risk FISH and lack of deep response had poor outcomes. ClinicalTrials.gov identifier: (NCT02916771)

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“…Among the remaining 37 genes, we discovered classic markers for CD8 + naive cells (TCF7 [ 25 , 26 ], LEF1 [ 25 ], BACH2 [ 27 ], BCL11B [ 28 ], and THEMIS [ 29 ]), which have been previously described in the literature (Fig. 3B ).…”

Section: Resultsmentioning

confidence: 99%

Machine Learning Made Easy (MLme): a comprehensive toolkit for machine learning–driven data analysis

Akshay,

Katoch,

Shekarchizadeh

et al. 2024

GigaScience

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Background Machine learning (ML) has emerged as a vital asset for researchers to analyze and extract valuable information from complex datasets. However, developing an effective and robust ML pipeline can present a real challenge, demanding considerable time and effort, thereby impeding research progress. Existing tools in this landscape require a profound understanding of ML principles and programming skills. Furthermore, users are required to engage in the comprehensive configuration of their ML pipeline to obtain optimal performance. Results To address these challenges, we have developed a novel tool called Machine Learning Made Easy (MLme) that streamlines the use of ML in research, specifically focusing on classification problems at present. By integrating 4 essential functionalities—namely, Data Exploration, AutoML, CustomML, and Visualization—MLme fulfills the diverse requirements of researchers while eliminating the need for extensive coding efforts. To demonstrate the applicability of MLme, we conducted rigorous testing on 6 distinct datasets, each presenting unique characteristics and challenges. Our results consistently showed promising performance across different datasets, reaffirming the versatility and effectiveness of the tool. Additionally, by utilizing MLme’s feature selection functionality, we successfully identified significant markers for CD8+ naive (BACH2), CD16+ (CD16), and CD14+ (VCAN) cell populations. Conclusion MLme serves as a valuable resource for leveraging ML to facilitate insightful data analysis and enhance research outcomes, while alleviating concerns related to complex coding scripts. The source code and a detailed tutorial for MLme are available at https://github.com/FunctionalUrology/MLme.

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Themis suppresses the effector function of CD8+ T cells in acute viral infection

Cited by 6 publications

References 51 publications

Themis controls T cell activation, effector functions, and metabolism of peripheral CD8⁺T cells

Themis controls T cell activation, effector functions, and metabolism of peripheral CD8⁺T cells

Long-Term Follow-Up Defines the Population That Benefits from Early Interception in a High-Risk Smoldering Multiple Myeloma Clinical Trial Using the Combination of Ixazomib, Lenalidomide, and Dexamethasone

Machine Learning Made Easy (MLme): a comprehensive toolkit for machine learning–driven data analysis

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Themis suppresses the effector function of CD8+ T cells in acute viral infection

Cited by 6 publications

References 51 publications

Themis controls T cell activation, effector functions, and metabolism of peripheral CD8+T cells

Themis controls T cell activation, effector functions, and metabolism of peripheral CD8+T cells

Long-Term Follow-Up Defines the Population That Benefits from Early Interception in a High-Risk Smoldering Multiple Myeloma Clinical Trial Using the Combination of Ixazomib, Lenalidomide, and Dexamethasone

Machine Learning Made Easy (MLme): a comprehensive toolkit for machine learning–driven data analysis

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Themis controls T cell activation, effector functions, and metabolism of peripheral CD8⁺T cells

Themis controls T cell activation, effector functions, and metabolism of peripheral CD8⁺T cells