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Acute CD8+ T cell responses to viral infection harbor Tcf1-dependent stem-like cells that quantitatively yield central memory [ATAC-seq]

ABSTRACT: Central memory CD8+ T cells (TCM) can protect from secondary pathogen infection, from chronic infection and cancer as a result of their stem cell-like properties. However, the developmental origin of central memory cells and consequently the basis of their stemness have not been resolved. By monitoring the expression of the transcription factor Tcf1 (Tcf7), which is essential for central memory formation, we identified a small subset of CD8+ T cells present during the acute response to primary infection. These cells lacked cytotoxic effector function, resembled TCM both transcriptionally and epigenetically, had stem cell-like properties, and quantitatively yielded TCM. Stemness effector phase Tcf7+ CD8+ T cells depended on Tcf1 protein expression and on a set of Tcf1-dependent genes associated with adult stem cells. Stemness was thus not acquired subsequent to antigen clearance but was maintained in rare CD8+ T cells responding to acute infection and these cells quantitatively yielded TCM.

ORGANISM(S): Mus musculus

PROVIDER: GSE144382 | GEO | 2020/10/30

REPOSITORIES: GEO

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Acute CD8+ T cell responses to viral infection harbor Tcf1-dependent stem-like cells that quantitatively yield central memory [RNA-seq]

Project description:Central memory CD8+ T cells (TCM) can protect from secondary pathogen infection, from chronic infection and cancer as a result of their stem cell-like properties. However, the developmental origin of central memory cells and consequently the basis of their stemness have not been resolved. By monitoring the expression of the transcription factor Tcf1 (Tcf7), which is essential for central memory formation, we identified a small subset of CD8+ T cells present during the acute response to primary infection. These cells lacked cytotoxic effector function, resembled TCM both transcriptionally and epigenetically, had stem cell-like properties, and quantitatively yielded TCM. Stemness effector phase Tcf7+ CD8+ T cells depended on Tcf1 protein expression and on a set of Tcf1-dependent genes associated with adult stem cells. Stemness was thus not acquired subsequent to antigen clearance but was maintained in rare CD8+ T cells responding to acute infection and these cells quantitatively yielded TCM.

2020-10-30 | GSE142409 | GEO

Formation and fate of stem-cell like Tcf7+ CD8+ T cells during a primary immune response to viral infection [scRNA-seq]

Project description:In response to infection, naïve CD8+ T cells (Tn) expand and differentiate into short-lived terminal effector (Tte) cells, which eliminate infected cells, or into central memory (Tcm) cells, which persist following pathogen clearance and mediate protection against re-infection thanks to their stem cell-like properties. The stage-specific signals required for the cell fate changes have remained incompletely understood. Here we find that Tn cells, which express the transcription factor Tcf1 (Tcf7), yield Tcf1+ cells, which retain stem-like potential throughout the primary response and which quantitatively yield Tcf1+ Tcm cells following pathogen clearance. However, only the Tcf1+ cells present during priming are competent to yield Tcf1- Tte cells. Priming commits cells to undergo multiple divisions while maintaining Tcf1 expression. The presence of type I interferon during the division, rather than the priming phase suppresses Tcf1 expression. Tcf1 loss results in the stable loss of stemness, an event that precedes the stable acquisition of a Tte state. Thus, inflammatory cytokines drive Tte differentiation from dividing Tcf1+ cells, which are prone to become Tcm cells.

2023-11-06 | GSE221968 | GEO

Formation and fate of stem-cell like Tcf7+ CD8+ T cells during a primary immune response to viral infection [ATAC-seq]

2023-11-06 | GSE221967 | GEO

RNA-Seq analysis of Tcf7-deficient and -sufficient lung CD8+ TRM cells after influenza infection

Project description:T cell factor 1 (Tcf1, encoded by Tcf7) promotes the central memory CD8+ T cell (TCM) differentiation and homeostatic proliferation in lymphoid tissues. It remains unclear if and how Tcf1 regulates the CD103high tissue-resident memory CD8+ T cell (TRM) formation in non-lymphoid tissues. Using an influenza A infection mouse model, we collected Tcf7-deficient and -sufficient lung CD8+ TRM cells for RNA sequencing analysis.

2020-03-16 | GSE135309 | GEO

Tcf1 preprograms glycolysis mobilization in central memory CD8+ T cells in recall response

Project description:The goal of this study is to determine the impact of Tcf1 deficiency on recall capacity of central memory CD8+ T (Tcm) cells. We demonstrate that loss of Tcf1 shows limited impact on Tcm cells at resting state, but severely comprimises activation of glycolysis and other key regulators during recall response. Based on these findings, we propose that Tcf1 preprograms the responsiveness of Tcm cells to secondary challenges.

2021-11-10 | GSE177064 | GEO

Regulation of CD8 T cell differentiation by the RNA-binding protein DDX5

Project description:The RNA-binding protein DDX5 is a polyfunctional regulator of gene expression, but its role in CD8+ T cell biology has not been extensively investigated. In this study, we demonstrate that deletion of DDX5 reduced differentiation of terminal effector (TE), effector memory (TEM), and terminal effector memory (t-TEM) cells while increasing the generation of central memory (TCM) cells; forced expression of DDX5 elicited the opposite phenotype. DDX5-deficient CD8+ T cells exhibited increased expression of genes that promote TCM cell differentiation, including Tcf7 and Eomes. Together, these findings reveal a role for DDX5 in regulating the differentiation of effector and memory CD8+ T cell subsets in response to microbial infection.

2023-05-23 | GSE230028 | GEO

Memory-like CD8 T-cells sustain the immune response to chronic viral infections.

Project description:We have discovered a small subpopulation of virus-specific CD8 T-cells that sustains the T-cell response in chronic infections. These cells are defined by - and depend on - the expression of the transcription factor Tcf1 (T cell factor 1) and show key characteristics of central memory cells while lacking an effector signature. Unlike conventional memory cells, Tcf1+ T-cells display hallmarks of an âexhaustedâ phenotype, including the expression of certain inhibitory receptors. Naive Tcf1-GFP+ P14 cells (Naive) were transferred into Vb5 recipient mice (CD45.1) prior to infection with LCMV clone 13 (c13). Tcf1-GFP+ P14 cells (chronic Tcf1+) and Tcf1-GFP- P14 cells (chronic Tcf1-) were flow sorted on day 28 post infection. Naive Tcf1-GFP+ P14 cells (Naive) were also transferred into C57BL/6 hosts (CD45.1.2) prior to infection with LCMV Armstrong (Arm). Tcf1-GFP+ P14 cells (memory Tcf1+) and Tcf1-GFP- P14 cells (memory Tcf1-) were flow sorted on day 28 post infection. Total RNA was extracted, cDNA libraries prepared and sequencing was performed using Illumina HiSeq 2500 technology.

2016-08-22 | E-GEOD-83978 | biostudies-arrayexpress

Expression of miRNAs in human ex-vivo CD8+ T cell subsets

Project description:The aim was to assess miRNA expression in 3 human ex-vivo CD8+ T cell subsets which span from antigen inexperienced cells (NaM-CM-/ve) to early memory cells (central memory, Tcm) and later stage memory cells (effector memory, Tem) CD8+ T cells were sorted on a FACS Aria II machine. N = naM-CM-/ve = CD8+, CCR7+, CD45RA+, CD45RO-, Tcm = central memory = CD8+, CCR7+, CD45RA-, CD45RO-,Tem= effector memory = CD8+, CCR7-, CD45RA-, CD45RO+ PBMC were isolated from 3 healthy human donors and sorted by FACS into 3 CD8+ T cell subsets. Total RNA was purified using the miRVANA kit (Ambion)

2014-10-24 | E-GEOD-54867 | biostudies-arrayexpress

Impact of Bcl11b on the transcriptome of CD8+ T cell subsets[RNA-seq]

Project description:The transcription factor (TF) networks that regulate the differentiation of resident versus circulating memory CD8+ T cells are incompletely understood. Here we show that the TF Bcl11b restricts gut resident memory (Trm) cell differentiation, while promoting splenic T central memory (Tcm) and effector memory (Tem) cell differentiation. The reduction of Bcl11b-deficient splenic Tcm and Tem cells was not due to major alterations in their programs, but rather due to the increased homing of their precursors to the small intestine. However, Bcl11b-deficient resident memory precursor cells upregulated residency program, including the TFs Ahr and Prdm1 (encoding Blimp1), and downregulated Tcf7, which restricts the residency program and promotes tissue egress. Bcl11b directly bound at Ahr and Prdm1, as well as at Tcf7 genes. Abrogating Ahr and Prdm1, or restoration of Tcf7 expression in Bcl11b-deficient cells led to partial correction of the excessive resident memory cell differentiation. Functionally, Bcl11b-deficient memory CD8+ T cells had an impaired recall response, but anti-tumor immunity was increased in adoptive cell therapy. Bcl11b also repressed the residency program in human CD8+ T cells and human Bcl11b low tumor-infiltrating lymphocytes showed increased residency gene expression. Thus, Bcl11b plays a critical role in balancing the circulating and tissue residency programs and reveals a potential novel target for cancer immunotherapies.

2023-06-08 | GSE186283 | GEO

Mapping Bcl11b binding in in vitro differentiated resident memory T cells [ChIP-seq]

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