tumor-transplantation-for-assessing-dynamics-tumor-infiltrating-cd8-t

Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8<sup>+</sup> T Cells in Mice

T cell-mediated immunity plays a crucial role in immune responses against tumors, with cytotoxic T lymphocytes (CTLs) playing the leading role in ...

Third Military Medical University

Follicular helper CD4 T (T) cells are critical for optimal B-cell-mediated humoral immunity by initiating, fueling, and sustaining germinal center reactions. The differentiation of T cells relies on multiple intrinsic and extrinsic factors; however, the details by which these factors are integrated to coordinate T differentiation are largely unknown. In this study, using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) viral infection, we demonstrate that mTOR complex 2 (mTORC2) kinase integrates TCR signaling and ICOS-mediated co-stimulation to promote late differentiation and functional maturation of virus-specific T cells. Specifically, mTORC2 functions to maintain T lineage specifications, including phenotypes, migratory characteristics, and functional properties. Thus, our results highlight the importance of mTORC2 in guarding T phenotypic and functional maturation.

The Kinase Complex mTOR Complex 2 Promotes the Follicular Migration and Functional Maturation of Differentiated Follicular Helper CD4 T Cells During Viral Infection.

The long-term persistence of viral antigens drives virus-specific CD8 T cell exhaustion during chronic viral infection. Yet exhausted, CD8 T cells are still endowed with certain levels of effector function, by which they can keep viral replication in check in chronic infection. However, the regulatory factors involved in regulating the effector function of exhausted CD8 T cell are largely unknown. Using mouse model of chronic LCMV infection, we found that the deletion of transcription factor TCF-1 in LCMV-specific exhausted CD8 T cells led to the profound reduction in cytokine production and degranulation. Conversely, ectopic expression of TCF-1 or using agonist to activate TCF-1 activities promotes the effector function of exhausted CD8 T cells. Mechanistically, TCF-1 fuels the functionalities of exhausted CD8 T cells by promoting the expression of an array of key effector function-associated transcription regulators, including Foxo1, Zeb2, Id3, and Eomes. These results collectively indicate that targeting TCF-1 mediated transcriptional pathway may represent a promising immunotherapy strategy against chronic viral infections by reinvigorating the effector function of exhausted virus-specific CD8 T cells.

The Transcription Factor TCF1 Preserves the Effector Function of Exhausted CD8 T Cells During Chronic Viral Infection.

Epigenetic modifications to histones dictate the differentiation of naïve CD4 T cells into different subsets of effector T helper (T) cells. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the mechanism regulating the differentiation of T1, T2 and regulatory T (T) cells. However, whether and how EZH2 regulates follicular helper T (T) cell differentiation remain unknown. Using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection, we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific T cells compared to those in T1 cells. Ablation of EZH2 in LCMV-specific CD4 T cells leads to a selective impairment of early T cell fate commitment, but not late T differentiation or memory T maintenance. Mechanistically, EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for T fate commitment, particularly B cell lymphoma 6 (Bcl6), and thus directs T cell commitment. Therefore, we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early T differentiation during acute viral infection.

The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection.

Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor.

The protection of a majority of viral vaccines is mediated by CD4 T cell-dependent humoral immunity. The methyltransferase enhancer of zeste homolog 2 (EZH2) dictates the differentiation of naive CD4 T cells into distinct effector T helper subsets at the onset of acute viral infection. However, whether and how EZH2 manipulates differentiated virus-specific CD4 T cell expansion remain to be elucidated. Here, we found that EZH2 is integral for virus-specific CD4 T cell expansion in a mouse model of acute viral infection. By a mechanism that involves fine-tuning the mechanistic target of rapamycin (mTOR) signaling, EZH2 participates in integrating metabolic pathways to support cell expansion. The genetic ablation of EZH2 leads to impaired cellular metabolism and, consequently, poor CD4 T cell response to acute viral infection. Thus, we identified EZH2 as a novel regulator in virus-specific CD4 T cell expansion during acute viral infection. The CD4 T cell response is critical in curtailing viral infection or eliciting efficacious viral vaccination. Highly efficient expansion of virus-specific CD4 T cells culminates in a qualified CD4 T cell response. Here, we found that the epigenetic regulator EZH2 is a prerequisite for the virus-specific CD4 T cell response, with a mechanism coupling cell expansion and metabolism. Thus, our study provides valuable insights for strategies targeting EZH2 to improve the efficacy of CD4 T cell-based viral vaccines and to help treat diseases associated with aberrant CD4 T cell responses.

The Epigenetic Regulator EZH2 Instructs CD4 T Cell Response to Acute Viral Infection via Coupling of Cell Expansion and Metabolic Fitness.

The efficient induction and long-term persistence of pathogen-specific memory CD8 T cells are pivotal to rapidly curb the reinfection. Recent studies indicated that long-noncoding RNAs expression is highly cell- and stage-specific during T cell development and differentiation, suggesting their potential roles in T cell programs. However, the key lncRNAs playing crucial roles in memory CD8 T cell establishment remain to be clarified. Through CD8 T cell subsets profiling of lncRNAs, this study found a key lncRNA-Snhg1 with the conserved naive-effector-memory expression pattern in CD8 T cells of both mice and human, that can promote memory formation while impeding effector CD8 in acute viral infection. Further, Snhg1 was found interacting with the conserved vesicle trafficking protein Vps13D to promote IL-7Rα membrane location specifically. With the deep mechanism probing, the results show Snhg1-Vps13D regulated IL-7 signaling with its dual effects in memory CD8 generation, which not just because of the sustaining role of STAT5-BCL-2 axis for memory survival, but more through the STAT3-TCF1-Blimp1 axis for transcriptional launch program of memory differentiation. Moreover, we performed further study with finding a similar high-low-high expression pattern of human SNHG1/VPS13D/IL7R/TCF7 in CD8 T cell subsets from PBMC samples of the convalescent COVID-19 patients. The central role of Snhg1-Vps13D-IL-7R-TCF1 axis in memory CD8 establishment makes it a potential target for improving the vaccination effects to control the ongoing pandemic.

Article	Year
The Kinase Complex mTOR Complex 2 Promotes the Follicular Migration and Functional Maturation of Differentiated Follicular Helper CD4 T Cells During Viral Infection. Frontiers in immunology\| PubMed ID: 29875775	2018
The Transcription Factor TCF1 Preserves the Effector Function of Exhausted CD8 T Cells During Chronic Viral Infection. Frontiers in immunology\| PubMed ID: 30814995	2019
The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection. Cellular & molecular immunology\| PubMed ID: 30842630	2019
Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor. Cellular & molecular immunology\| PubMed ID: 32313207	2020
The Epigenetic Regulator EZH2 Instructs CD4 T Cell Response to Acute Viral Infection via Coupling of Cell Expansion and Metabolic Fitness. Journal of virology\| PubMed ID: 32999031	2020
The lncRNA Snhg1-Vps13D vesicle trafficking system promotes memory CD8 T cell establishment via regulating the dual effects of IL-7 signaling. Signal transduction and targeted therapy\| PubMed ID: 33758164	2021

Qin Tian

Biography

JoVE Journal Publications

Other Publications