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

To investigate the construction of the histological section datasets in the basal ganglia of digitized human brain to provide a reference for the meso-level histological data acquisition. A fresh adult brain from a cadaver with no neurological disease was selected, and tissue blocks of the basal ganglia in the right hemisphere was extracted using the visualization method, followed by pretreatments including gradient dehydrating, gelatin-embedding and setting of calibration points. And then the tissue blocks was cryosectioned into 60-μm-thick coronal sections and the sectional images were captured simultaneously by a digital camera at a fixed position. Two series of sections (one section out of ten) were Nissl-stained with Toluidine blue and immunostained with the calbindin D-28K, respectively. Stained sections were digitized by a high resolution scanner. After alignment and registration, contours of nuclei and different nucleic function divisions in the digital images of stained sections were identified, and then were segmented and labeled using software exploited by ourselves. Datasets of one set of registrated serial sectional images and two sets of registrated histochemically stained images in basal ganglia area were obtained, which provide a histological reference for the neurosurgery and diagnostic imaging. a systematic method of cutting, slicing, staining, data acquisition and image registration of large tissue blocks was established, providing a reference for histological data acquisition on the digital human. Anat Rec, 300:1011-1021, 2017. © 2016 Wiley Periodicals, Inc.

A Novel Method for Constructing Histological Section Datasets of the Basal Ganglia in Digitized Human Brain.

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.

Follicular helper T cells (TFH cells), known as the primary "helpers" of the germinal center (GC) reaction, promote the humoral immune response to defend against various pathogens. Under conditions of infection by different types of pathogens, many shared transcription factors (TFs), such as Bcl-6, TCF-1, and Maf, are selectively enriched in pathogen-specific TFH cells, orchestrating TFH cell differentiation and function. In addition, TFH cells also coexpress environmentally associated TFs as their conventional T cell counterparts (such as T-bet, GATA-3, or ROR-γt, which are expressed in Th1, Th2, or Th17 cells, respectively). These features likely indicate both the lineage-specificity and environmental adaption of the TFH cell responses. However, the extent to which the TFH cell response relies on these environmentally specific TFs is not completely understood. Here, we found that T-bet was specifically expressed in Type I TFH cells but not Type II TFH cells. While dispensable for the early fate commitment of TFH cells, T-bet was essential for the maintenance of differentiated TFH cells, promoting their proliferation, and inhibiting their apoptosis during acute viral infection. Microarray analysis showed both similarities and differences in transcriptome dependency on T-bet in TFH and TH1 cells, suggesting the distinctive role of T-bet in TFH cells. Collectively, our findings reveal an important and specific supporting role for T-bet in type I TFH cell response, which can help us gain a deeper understanding of TFH cell subsets.

The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection.

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.

Article	Year
A Novel Method for Constructing Histological Section Datasets of the Basal Ganglia in Digitized Human Brain. Anatomical record (Hoboken, N.J. : 2007)\| PubMed ID: 27981802	2017
The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection. Cellular & molecular immunology\| PubMed ID: 30842630	2019
The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection. Frontiers in immunology\| PubMed ID: 30984183	2019
Bcl6 Preserves the Suppressive Function of Regulatory T Cells During Tumorigenesis. Frontiers in immunology\| PubMed ID: 32477338	2020

Luoyingzi Xie

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