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HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE237813 | GEO | 2023/07/24

REPOSITORIES: GEO

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HMGB2 regulates the differentiation and stemness of exhausted CD8<sup>+</sup> T cells during chronic viral infection and cancer.

Project description:Chronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8+ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8+ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during chronic viral infection and in tumors. Despite Hmgb2-/- CD8+ T cells expressing TCF-1 and TOX, these master regulators were unable to sustain Tpex differentiation and long-term survival during persistent antigen. Furthermore, HMGB2 also had a cell-intrinsic function in the differentiation and function of memory CD8+ T cells after acute viral infection. Our findings show that HMGB2 is a key regulator of CD8+ T cells and may be an important molecular target for future T cell-based immunotherapies.

| S-EPMC10499904 | biostudies-literature

HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer [RNA-seq]

Project description:Transcriptional and epigenetic features were detected in WT versus HMGB2-/- P14 T cells following LCMV Arm and Cl13 infection.

2023-07-24 | GSE237812 | GEO

HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer [ATAC-seq]

Project description:Transcriptional and epigenetic features were detected in WT versus HMGB2-/- P14 T cells following LCMV Arm and Cl13 infection.

2023-07-24 | GSE237811 | GEO

HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer.

Project description:HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer.

| PRJNA996657 | ENA

HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer [RNA-seq]

Project description:HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer [RNA-seq]

| PRJNA996659 | ENA

HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer [ATAC-seq]

Project description:HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer [ATAC-seq]

| PRJNA996658 | ENA

Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection.

Project description:CD4 T cells play a critical role in regulating CD8 T-cell responses during chronic viral infection. Several studies in animal models and humans have shown that the absence of CD4 T-cell help results in severe dysfunction of virus-specific CD8 T cells. However, whether function can be restored in already exhausted CD8 T cells by providing CD4 T-cell help at a later time remains unexplored. In this study, we used a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Adoptive transfer of LCMV-specific CD4 T cells into chronically infected mice restored proliferation and cytokine production by exhausted virus-specific CD8 T cells and reduced viral burden. Although the transferred CD4 T cells were able to enhance function in exhausted CD8 T cells, these CD4 T cells expressed high levels of the programmed cell death (PD)-1 inhibitory receptor. Blockade of the PD-1 pathway increased the ability of transferred LCMV-specific CD4 T cells to produce effector cytokines, improved rescue of exhausted CD8 T cells, and resulted in a striking reduction in viral load. These results suggest that CD4 T-cell immunotherapy alone or in conjunction with blockade of inhibitory receptors may be a promising approach for treating CD8 T-cell dysfunction in chronic infections and cancer.

| S-EPMC3248546 | biostudies-literature

HDAC1 regulates effector CD8+ T cell differentiation during chronic viral infection

Project description:Hdac1 is a known epigenetic regulator of gene expression. The aim of this study is to investigate whether Hdac1 influences CD8+ T cell fate during chronic infection. We demonstrate that the genetic ablation of Hdac1 reduces the generation of Tex-Int cells

2025-04-23 | GSE271531 | GEO

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

Project description: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.

| S-EPMC6381939 | biostudies-literature

Mcl-1 regulates effector and memory CD8 T-cell differentiation during acute viral infection.

Project description:Mcl-1, an anti-apoptotic member of Bcl-2 family maintains cell viability during clonal expansion of CD8 T cells, but the cell intrinsic role of Mcl-1 in contraction of effectors or the number of memory CD8 T cells is unknown. Mcl-1 levels decline during the contraction phase but rebound to high levels in memory CD8 T cells. Therefore, by overexpressing Mcl-1 in CD8 T cells we asked whether limiting levels of Mcl-1 promote contraction of effectors and constrain CD8 T-cell memory. Mcl-1 overexpression failed to affect CD8 T-cell expansion, contraction or the magnitude of CD8 T-cell memory. Strikingly, high Mcl-1 levels enhanced mTOR phosphorylation and augmented the differentiation of terminal effector cells and effector memory CD8 T cells to the detriment of poly-cytokine-producing central memory CD8 T cells. Taken together, these findings provided unexpected insights into the role of Mcl-1 in the differentiation of effector and memory CD8 T cells.

| S-EPMC4769930 | biostudies-literature

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