Similar Datasets
Project description:To identify the subsets of exhausted T cells and to analyze the transcriptional-metabolic programs alongside their developmental trajectories at single-cell resolution, we isolated CD44+ PD-1hi CD8+ T cells from chronically infected wild-type (WT) mice 21 days after infection with the ‘clone 13’ strain of lymphocytic choriomeningitis virus (LCMV) by FACs sorting aand performed scRNA-sequencing.
2023-09-22 | GSE214003 | GEO
Project description:Lymphocytic choriomeningitis virus (LCMV) is the prototypic arenavirus and a natural mouse pathogen. LCMV Armstrong, an acutely resolved strain, and LCMV Clone 13, a mutant that establishes chronic infection, have provided contrasting infection models that continue to inform the fundamental biology of T cell differentiation, regulation of exhaustion, and response to checkpoint blockade. Here, we report the isolation and characterization of LCMV Minnesota (LCMV-MN), which was naturally transmitted to laboratory mice upon cohousing with pet shop mice and shares 80-95% amino acid homology with previously characterized LCMV strains. Infection of laboratory mice with purified LCMV-MN resulted in viral persistence that was intermediate between LCMV Armstrong and Clone 13, with widely disseminated viral replication and viremia that was controlled within 15-30 days, unless CD4 T cells were depleted prior to infection. LCMV-MN responding CD8+ T cells biased differentiation towards the recently described PD1+ CXCR5+ Tim-3lo stem-like CD8+ T cell population (also referred to as T exhausted progenitors, Tpex) that effectuates responses to PD-1 blockade checkpoint inhibition, a therapy that rejuvenates responses against chronic infections and cancer. This subset resembled previously characterized PD1+ TCF1+ stem-like CD8+ T cells by transcriptional, phenotypic, and functional assays, yet was atypically abundant. LCMV-MN may provide a tool to better understand the breadth of immune responses in different settings of chronic antigen stimulation as well as the ontogeny of T exhausted progenitors and the regulation of responsiveness to PD-1 blockade.
2022-08-22 | GSE207983 | GEO
Project description:Antigen-specific effector CD8+ T cells deficient in Blimp-1 (Prdm1) do not acquire maximal effector functions, evade terminal differentiation, and more rapidly acquire some hallmark properties of memory CD8+ T cells. In this study, we compared the gene expression profiles of wildtype and Prdm1-/- LCMV-specific effector CD8+ T cells to better understand the molecular mechanisms underlying this striking phenotype. DNA microarray analysis was performed of DbGP33-41 and DbNP396-404 tetramer-positive effector CD8+ T cells FACS-sorted at day 8 post-LCMV infection from four independent samples of either Blimp-1 conditional knockout mice (CKO; Blimp-1flox/flox x GranzymeB-cre+) or wildtype (WT) littermate controls.
2010-08-19 | E-GEOD-17211 | biostudies-arrayexpress
Project description:Infection with acute and chronic strains of LCMV (Armstrong (ARM) and Clone 13 (C13), respectively) leads to massive proliferation of monocytic cells contemporaneously with peak of the anti-viral CD8+ T cell response. These cells return to naïve levels following ARM infection. However, during C13 infection these cells are sustained at high levels and gain a T cell suppressive function at day 14 post infection. The mechanisms by which these cells are induced to proliferate and impair T cell function during chronic LCMV infection are largely unknown. To address this, we analyzed gene expression profiles using microarray analysis of purified splenic monocytic cells (CD11b+ Ly6Chi Gr-1low) from naïve mice, or day 14 LCMV ARM or LCMV C13 infected mice.
2013-02-25 | GSE43896 | GEO
Project description:In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, ex vivo treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after ex vivo IL-15 treatment compared with those before treatment revealed upregulation of ribosome-related genes and downregulation of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon ex vivo IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.
2023-05-30 | GSE233388 | GEO
Project description:Antigen-specific effector CD8+ T cells deficient in Blimp-1 (Prdm1) do not acquire maximal effector functions, evade terminal differentiation, and more rapidly acquire some hallmark properties of memory CD8+ T cells. In this study, we compared the gene expression profiles of wildtype and Prdm1-/- LCMV-specific effector CD8+ T cells to better understand the molecular mechanisms underlying this striking phenotype.
2009-07-22 | GSE17211 | GEO
Project description:During acute viral infections, naïve CD8+ T cells differentiate into effector CD8+ T cells and, after viral control, into memory CD8+ T cells. Memory CD8+ T cells are highly functional, proliferate rapidly upon reinfection and persist long-term without antigen. In contrast, during chronic infections, CD8+ T cells become “exhausted” and have poor effector function, express multiple inhibitory receptors, possess low proliferative capacity, and cannot persist without antigen. Exhuasted CD8+ T cells can be further segregated by their expression of the inhibitory cell surface receptor PD-1. We performed transcriptional profiling on both PD-1 High and PD-1 Intermediate H2-Db GP33-specific CD8+ T cells. H2-Db GP33-specific CD8+ T cells were sorted from C57BL/6 mice 30 days p.i. with LCMV clone 13. These cells were then segregated by their expression of the inhibitory cell surface receptor PD-1 into PD-1 High and PD-1 Intermediate subpopulations. We performed transcriptional profiling on these subpopulations.
2014-10-24 | E-GEOD-41869 | biostudies-arrayexpress
Project description:We report the transcriptome of subsets of mouse splenic mesenchymal reticular cells and lymph node reticular cells obtained from healthy Ccl19-cre x R26R-EYFP mice on a C57BL/6 background. We also examine splenic reticular cells from these mice infected with lymphocytic choriomeningitis virus (LCMV) strain Armstrong (acute infection) or strain Clone 13 (chronic infection). Subsets of CD45- CD31- Ter119- reticular cells were analyzed including PDPN+ T zone reticular cells (TRC) and MAdCAM-1+ marginal reticular cells (MRC) from spleen and lymph nodes. Additionally from the spleen we analyzed PDPN+ CD140a- cells, PDPN+ EYFP- cells, and EYFP+ red pulp reticular cells (RPRC) in healthy mice. We analyzed TRC, MRC, PDPN+ EYFP- cells, and EYFP+ RPRC from mice infected with LCMV Armstrong or LCMV Clone-13 on day 8 or on day 30 after infection. Our study represents the first detailed analysis of splenic reticular cell transcriptomes in healthy and LCMV-infected mice, with biologic replicates, generated by RNA-sequencing. We find substantial differential gene expression across subsets of splenic and lymph node reticular cells. We reveal significant changes in gene expression induced after virus infection that differ markedly with disease.
2022-01-09 | GSE171124 | GEO
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
Project description:T cell dysfunction is an important feature of many chronic viral infections. In particular, it was shown that PD-1 regulates T cell dysfunction during chronic LCMV infection in mice and PD-1 high cells exhibit an intense exhausted gene signature. These findings were extended to human chronic infections such as HIV, HCV and HBV. However, it is not known if PD-1 high cells of healthy humans have the traits of exhausted cells. In this study, we provide a comprehensive description of phenotype, function and gene expression profiles of PD-1 high versus PD-1 low CD8 T cells in the peripheral blood of healthy human adults as following: 1) The percentage of naive and memory CD8 T cells varied widely in the peripheral blood cells of healthy humans and PD-1 was expressed by the memory CD8 T cells. 2) PD-1 high CD8 T cells in healthy humans did not significantly correlated with the PD-1 high exhausted gene signature of HIV specific human CD8 T cells or chronic LCMV specific CD8 T cells from mice. 3) PD-1 expression did not directly affect the ability of CD8 T cells to secrete cytokines in healthy adults. 4) PD-1 was expressed by the effector memory (TEM) compared to ‘terminally differentiated effector’ (TEMRA) CD8 T cells. 5) Finally, an interesting inverse relationship between CD45RA and PD-1 expression was observed. We used highly purified PD-1 high and PD-1 low from six healthy adult individuals and naive CD8 T cell populations from four of those individuals for gene expression studies
2011-01-11 | E-GEOD-26495 | biostudies-arrayexpress