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

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.

During viral infection, virus-specific follicular helper T cells provide important help to cognate B cells for their survival, consecutive proliferation and mutation and eventual differentiation into memory B cells and antibody-secreting plasma cells. Similar to Tfh cells generated in other conditions, the differentiation of virus-specific Tfh cells can also be characterized as a process involved multiple factors and stages, however, which also exhibits distinct features. Here, we mainly focus on the current understanding of Tfh fate commitment, functional maturation, lineage maintenance and memory transition and formation in the context of viral infection.

Molecular Basis of the Differentiation and Function of Virus Specific Follicular Helper CD4 T Cells.

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.

T follicular helper (T) cells are crucial for effective humoral immunity by providing the required signals to cognate B cells and promoting germinal center (GC) formation. Many intrinsic and extrinsic factors have been reported to be involved in the multistage, multifactorial differentiation process of T cells. By comparing gene expression between T cells and T1 cells based on published GEO data, we found selective and high expression of sclerostin domain-containing protein 1 (SOSTDC1) in T cells but not in T1 cells; however, it is unclear whether SOSTDC1 is important for the differentiation and/or function of T cells. Using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection, we confirmed the selective expression of SOSTDC1 in T cells compared to that in T1 cells, but the ablation of SOSTDC1 did not affect T cell differentiation or effector function. Thus, our results indicate that the SOSTDC1 protein is merely a specific marker of T cells but does not play a functional role in the differentiation of T cells during acute viral infection.

Sclerostin domain-containing protein 1 is dispensable for the differentiation of follicular helper and follicular regulatory T cells during acute viral infection.

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

During tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3 cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.

Bcl6 Preserves the Suppressive Function of Regulatory T Cells During Tumorigenesis.

COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection. It is currently unknown as to the correlation between the magnitude of neutralizing antibody (NAb) responses and the disease severity in COVID-19 patients. In a cohort of 59 recovered patients with disease severity including severe, moderate, mild, and asymptomatic, we observed the positive correlation between serum neutralizing capacity and disease severity, in particular, the highest NAb capacity in sera from the patients with severe disease, while a lack of ability of asymptomatic patients to mount competent NAbs. Furthermore, the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-to-moderate symptoms. These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity, highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.

Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19.

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 adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is elusive. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity (mild, n = 10, moderate, n = 32, severe, n = 12) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and prolonged humoral immunity, assessed by GC response indicators including follicular helper T (T) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific T1 and CD8 T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated T responses; however, the virus-specific T1 and CD8 T cells were minimally induced in these patients. These results, therefore, uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of effective COVID-19 vaccines.

Article	Year
The Transcription Factor TCF1 Preserves the Effector Function of Exhausted CD8 T Cells During Chronic Viral Infection. Frontiers in immunology\| PubMed ID: 30814995	2019
Molecular Basis of the Differentiation and Function of Virus Specific Follicular Helper CD4 T Cells. Frontiers in immunology\| PubMed ID: 30828337	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
Sclerostin domain-containing protein 1 is dispensable for the differentiation of follicular helper and follicular regulatory T cells during acute viral infection. American journal of translational research\| PubMed ID: 31312383	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
Bcl6 Preserves the Suppressive Function of Regulatory T Cells During Tumorigenesis. Frontiers in immunology\| PubMed ID: 32477338	2020
Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19. Signal transduction and targeted therapy\| PubMed ID: 32879307	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 dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity. Signal transduction and targeted therapy\| PubMed ID: 33686064	2021

Jianfang Tang

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