Chronic lymphocytic leukemia skews antigen-specific CD8 T cells leading to dysfunctional memory response
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185387 | GEO | 2023/01/19
REPOSITORIES: GEO
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2017-02-21 | GSE79805 | GEO
Project description:Purpose: ATAC-seq analysis of naive and three effector OT-I cell subsets (from a Klrg1-Cre fate reporter mouse model) isolated from the spleen of C57BL/6 mice 0 and 8 days post infection with OVA-expressing Listeria monocytogenes. The hypothesis tested in the present study was that chromatin remodeling in KLRG1+ effector CD8 T lymphocytes promotes the differentiation into KLRG1- memory CD8 T lymphocytes that provide long-lasting immunity against infectious diseases and malignancies. Methods: DNA was obtained from 50,000 FACS-purified OT-I cell subsets isolated from spleen 0 and 8 days post infection with ovalbumin-expressing Listeria monocytogenes (LM-OVA) (experiment 3). Results: Using ATAC-seq technology, we analyzed the chromatin accessibility landscape of naive and three effector OT-I cells (KLRG1+ Reporter+, KLRG1- Reporter+ (exKLRG1) and KLRG1- Reporter-). Conclusions: Our study represents the first fate mapping analysis of KLRG1+ effector OT-I cells, demonstrates that KLRG1+ effector OT-I cells differentiate into all memory T cell lineages thereby promoting protective immunity. RNA-seq identified CX3CR1 as a marker of circulating exKLRG1 early memory OT-I cells, and ATAC-seq analysis revealed that chromatin remodeling enabled exKLRG1 memory cells to exhibit both a high cytotoxic and proliferative capacity.
2018-03-01 | GSE110876 | GEO
Project description:Reconstitution of cytomegalovirus (CMV)-specific immunity following transplant remains a primary clinical objective to prevent CMV disease, and adoptive immunotherapy of CMV-specific T cells can be an effective therapeutic approach. Due to the persistence of CMV, most CMV-specific CD8+ T cells become terminally differentiated effector cells (TEFF). However, a minor subset retains a memory phenotype (TM). Interestingly, recent studies suggest that CMV-specific CD8+ T cells with different phenotypes may have different abilities to reconstitute sustained immunity following transfer. The immunology of human CMV (HCMV) infections is reflected in the mouse model of MCMV infection. We found that HCMV- and MCMV-specific T cells displayed shared genetic programs, validating the MCMV model for studies of CMV-specific T cells in vivo. After transfer, the proliferative capacity of MCMV-specific TM cells was vastly superior to TEFF cells. Strikingly, TM cells expanded and established sustained and diverse T cell populations even after multiple challenges. Although both TEFF and TM cells could protect Rag-/- mice, only TM cells could consistently survive after transfer into immune replete, latently infected recipients and respond if recipient immunity was lost. These data show that CMV-specific TM cells retain memory function during persistent infection and can re-establish CMV immunity when necessary. C57BL/6 mice were infected intraperitoneally (i.p.) with MCMV strain MW97.01 between 6-16 weeks of age. Splenocytes were isolated from chronically-infected mice and co-stained with three PE-conjugated tetramers loaded with the antigenic peptides from M38, m139 and IE3, all of which promote memory inflation. Cells were then stained with fluorescently conjugated antibodies and sorted on a MoFlo cell sorter. Naïve CD8+ cells were identified as CD44lo. MCMV-specific T cells were identified as CD8+, CD44hi and tetramer binding and then further segregated into memory and effector cells subsets by their expression of KLRG1 and CD127.
2015-01-28 | E-GEOD-61927 | biostudies-arrayexpress
Project description:Purpose: RNA-seq analysis of three memory OT-I cell subsets (from a Klrg1-Cre fate reporter mouse model) isolated from the spleen of C57BL/6 mice infected with Listeria monocytogenes. The hypothesis tested in the present study was that KLRG1+ effector CD8 T lymphocytes differentiate into KLRG1- memory CD8 T lymphocytes and provide long-lasting immunity against infectious diseases and malignancies. Methods: Total RNA was obtained from FACS-purified OT-I cell subsets isolated from spleen 104 (experiment 1) and 110 days post infection (experiment 2) with ovalbumin-expressing Listeria monocytogenes (LM-OVA). Results: Using RNA-seq technology, we performed genome-wide transcriptional profiling of three memory OT-I cells (KLRG1+ Reporter+, KLRG1- Reporter+ (exKLRG1) and KLRG1- Reporter-) and identified 36 genes differentially expressed (> 1.5-fold) between exKLRG1 and KLRG1- Reporter- memory OT-I cells, and 132 differentially expressed genes between exKLRG1 and KLRG1+ Reporter+ memory OT-I cells. We then confirmed the expression of 15 genes/molecules by qRT-PCR and/or flow cytometry. Conclusions: Our study represents the first fate mapping analysis of KLRG1+ effector OT-I cells, demonstrates that KLRG1+ effector OT-I cells differentiate into all memory T cell lineages thereby promoting protective immunity. RNA-seq also identified CX3CR1 as a marker of circulating exKLRG1 early memory OT-I cells.
2018-03-01 | GSE110629 | GEO
Project description:Purpose: RNA-seq analysis of three memory OT-I cell subsets (from a Klrg1-Cre fate reporter mouse model) isolated from the spleen of C57BL/6 mice infected with vesicular stomatitis virus. The hypothesis tested in the present study was that KLRG1+ effector CD8 T lymphocytes differentiate into KLRG1- memory CD8 T lymphocytes and provide long-lasting immunity against infectious diseases and malignancies. Methods: Total RNA was obtained from FACS-purified OT-I cell subsets isolated from spleen 70 days post infection with ovalbumin-expressing vesicular stomatitis virus (VSV-OVA) (experiment 3). Results: Using RNA-seq technology, we performed genome-wide transcriptional profiling of three memory OT-I cells (KLRG1+ Reporter+, KLRG1- Reporter+ (exKLRG1) and KLRG1- Reporter-) and identified 36 genes differentially expressed (> 1.5-fold) between exKLRG1 and KLRG1- Reporter- memory OT-I cells, and 132 differentially expressed genes between exKLRG1 and KLRG1+ Reporter+ memory OT-I cells. We then confirmed the expression of 15 genes/molecules by qRT-PCR and/or flow cytometry. Conclusions: Our study represents the first fate mapping analysis of KLRG1+ effector OT-I cells, demonstrates that KLRG1+ effector OT-I cells differentiate into all memory T cell lineages thereby promoting protective immunity. RNA-seq also identified CX3CR1 as a marker of circulating exKLRG1 early memory OT-I cells.
2018-03-01 | GSE110706 | GEO
Project description:We compared the transcriptional profile of FACS-purified total effector, KLRG1+ effector and KLRG1- effector Lck-Cre;Ptpn2fl/fl and Ptpn2fl/fl OT-I cells from spleens of acutely infected mice. As expected, we found a large number of differentially expressed genes (DEG; |log2(fold-change)| >1; false discovery rate <0.05) between KLRG1– and KLRG1+ subsets of both Lck-Cre;Ptpn2fl/fl (712 DEG) and Ptpn2fl/fl (528 DEG) OT-I cells. Furthermore, we found 190 DEGs between total populations of Ptpn2-deficient and control OT-I cells. Considerably fewer genes were differentially expressed between Lck-Cre;Ptpn2fl/fl and Ptpn2fl/fl OT-I cells amongst the KLRG1– (93 DEG) and KLRG1+ (59 DEG) subsets. Hierarchical clustering analysis further revealed clustering of KLRG1– cells of both genotypes with total Ptpn2fl/fl OT-I cells, whereas KLRG1+ cells of both genotypes clustered with total Lck-Cre;Ptpn2fl/fl OT-I cells. Gene set enrichment analysis further showed that differential gene profiles between Lck-Cre;Ptpn2fl/fl and Ptpn2fl/fl OT-I cells for all subfractions (total, KLRG1+, KLRG1–) were enriched significantly for previously identified effector versus memory CD8+ T cell signature genes. Taken together, these findings indicate that after in vivo priming following HSV infection, Ptpn2 deficiency resulted in the preferential generation of OT-I cells with a transcriptional profile biased towards more terminally differentiated KLRG1+ effector cells with restricted memory potential.
2021-02-04 | GSE166133 | GEO
Project description:T lymphocytes responding to microbial infection give rise to effector cells that mediate acute host defense and memory cells that provide long-lived immunity, but the fundamental question of when and how these cells arise remains unresolved. Here we combine single-cell gene expression analyses with machine-learning approaches to trace the transcriptional roadmap of individual CD8+ T lymphocytes throughout the course of an immune response in vivo. Gene expression signatures predictive of eventual fates could be discerned as early as the first T lymphocyte division and may be influenced by asymmetric partitioning of the interleukin-2 receptor during mitosis. These findings underscore the importance of single-cell analyses in understanding fate determination and provide new insights into the specification of divergent lymphocyte fates early during an immune response to microbial infection. The goal of the study was to profile the gene expression in single CD8+ T cells responding in vivo to a microbial infection over multiple timepoints. 5 x 103 CD8+ CD45.1+ T cells transgenic for the OT-1 T cell receptor (which recognizes Listeria monocytogenes expressing ovalbumin (Lm-ova)) were adoptively transferred into congenic wild-type CD45.2 C57/B6J recipients, followed by infection intravenously one day later with 5 x 103 colony-forming units (CFU) of Lm-OVA. Splenocytes were isolated from recipient mice at 5, 7, or 45 days post-infection. To isolate cells at 3 days post-infection, 2 x 104 OT-1 CD8+ T cells were adoptively transferred. To isolate cells that had undergone their first division, 2 x 106 OT-1 CD8+ T cells were first labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE) prior to adoptive transfer and recipient mice were sacrificed at 48 hours post-infection. Unactivated naM-CM-/ve OT-1 CD45.1+ CD8+ T cells were also included. Cells were stained with fluorochrome-labeled antibodies against CD8, CD44, CD4, CD11b, CD11c, and F4/80, and sorted on a MoFlo (Beckman Coulter) or FACS Aria II (BD Biosciences) flow cytometer. The Ct value for each gene analyzed in each individual cell at each time point is reported in the Matrix non-normalized. The 94 ABI TaqMan Assay IDs are listed on the left (A2-A96), along with the accession number (B2-B96) and corresponding gene name (C2-C96) of each gene studied. The Il2 gene expression assay was duplicated. Each heading (D1-BCV)) represents a single cell from each of 13 timepoints or T cell subset that were profiled. The timepoints/T cell subsets and number of each cells profiled from each timepoint/T cell subset were: unactivated naM-CM-/ve (149 cells), distal daughter (48), proximal daughter (83), division 1 (144), day 3 post-infection (143), day 5 post-infection memory precursor (Tmp) (90), day 5 post-infection short-lived effector (Tsle) (79), day 5 post-infection (154), day 7 post-infection memory precursor Tmp (62), day 7 post-infection short-lived effector Tsle (89), day 7 post-infection (134), central memory Tcm (138), and effector memory Tem (136).
2014-03-02 | E-GEOD-54321 | biostudies-arrayexpress
Project description:Effector CD8 T-cell responses in chronic infection and cancer are maintained by proliferation competent progenitors, which share features with the progenitors of memory T-cells in acutely resolved infections. Combining classical assessment of population dynamics with single cell RNA-sequencing, we discovered a switch in the need for CD4 help between related populations in acute and chronic infection. While in acute infection memory T-cells but not effector T-cells are CD4 help dependent, we found the opposite in chronic infection. Thus, progenitor cells in chronic infection acquire a level of autonomous function that is not seen among their counterparts in acute infection. Vice versa, the dependece of the effector cells highlight why a functional antigen-specific CD4 T-cell compartment is critical in therapeutic settings.
2019-09-11 | GSE137007 | GEO
Project description:Innate and adaptive immune cells can acquire “memory” of encounters with a diverse range of activating signals to tune their response to secondary stimuli. Group 1 innate lymphoid cells (ILC1) are recently discovered tissue-resident sentinels that are essential for early host protection from intracellular pathogens at initial sites of infection. However, whether ILC1 function as short-lived effectors or persist and refine their responsiveness following pathogen challenge is not well understood. Furthermore, whether pathogen-derived antigens directly modulate tissue-resident ILC responses remains unclear. Here, we found that liver-resident ILC1 expand locally and persist following the resolution of mouse cytomegalovirus (MCMV) infection. MCMVexperienced ILC1 acquired stable transcriptional, epigenetic, and phenotypic changes, with an enhanced protective effector response to secondary MCMV challenge. Protective memory ILC1 responses were dependent on the MCMV-encoded glycoprotein m12, but not formed during bystander cytokine activation following heterologous infection. Thus, liver ILC1 acquire adaptive features in a MCMV-specific manner.
2019-05-02 | GSE128906 | GEO
Project description:Memory T cells provide immunity against pathogen reinvasion, but mechanisms of their long-term maintenance is unclear. Here we show that mice with the deletion of the transcription factor Foxo1 in activated CD8+ T cells had defective secondary but not primary responses to Listeria monocytogenes infection. Compared to short-lived effector T cells, memory precursor effector T cells expressed higher amounts of Foxo1 that promoted their generation and maintenance. Gene expression profiling and chromatin immunoprecipitation sequencing experiments revealed the chemokine receptor CCR7 and the transcription factor TCF1 as novel Foxo1-bound target genes with critical functions in memory T cell trafficking and transcriptional regulation. These findings demonstrate that Foxo1 is selectively incorporated into the genetic program that regulates memory but not effector CD8+ T cell responses to infection. Wild-type and GzmB-cre Foxo1fl/fl CD27hiKLRG1lo OT-I T cells were isolated by FACS sorting at 7 days post LM-OVA infection. RNA was prepared with the miRNeasy kit according to the manufacturer’s instructions (Qiagen). RNA amplification, labeling and hybridization to Mouse 430 2.0 Array chips (Affymetrix) were carried out at the Genomics Core Facility of Memorial Sloan-Kettering Cancer Center.
2013-05-16 | E-GEOD-46942 | biostudies-arrayexpress