Antioxidant metabolism in activated CD8+ T cells regulates stem-like human memory T cell formation and anti-tumor immunity
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ABSTRACT:
PROVIDER: PRJNA472586 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7203670.fastq.gz | Fastqsanger.gz | |||
| SRR7203671.fastq.gz | Fastqsanger.gz | |||
| SRR7203672.fastq.gz | Fastqsanger.gz | |||
| SRR7203673.fastq.gz | Fastqsanger.gz | |||
| SRR7203674.fastq.gz | Fastqsanger.gz |
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Project description:Adoptive T cell transfer (ACT) immunotherapy benefits from early-differentiated memory stem-like T (TSCM) cells capable to persist in the long term and to generate potent anti-tumor effectors. Due to their paucity ex vivo, TSCM can be derived from less differentiated naïve precursors but the molecular signals at the basis of their generation are ill-defined. We found that less differentiated human circulating CD8+ T cells display substantial antioxidant capacity ex vivo compared to more differentiated central and effector memory T cells. Limiting reactive oxygen species (ROS) metabolism with anti-oxidants during naïve T cell activation hindered terminal differentiation while allowing expansion and generation of TSCM cells. N-acetylcysteine, the most effective in this regard, induced a transcriptional network and a metabolic profile characteristic of self-renewing memory T cells. Upon ACT, the generated TSCM cells established long-term immunity in vivo and exerted more potent anti-tumor immunity in a xenogeneic model when redirected with CD19 CAR, highlighting the translational relevance of NAC as a simple and inexpensive method to improve ACT
2018-10-19 | GSE114765 | GEO
Project description:Adoptive T cell transfer (ACT) immunotherapy benefits from early differentiated stem cell memory T (Tscm) cells capable of persisting in the long term and generating potent antitumor effectors. Due to their paucity ex vivo, Tscm cells can be derived from naive precursors, but the molecular signals at the basis of Tscm cell generation are ill-defined. We found that less differentiated human circulating CD8+ T cells display substantial antioxidant capacity ex vivo compared with more differentiated central and effector memory T cells. Limiting ROS metabolism with antioxidants during naive T cell activation hindered terminal differentiation, while allowing expansion and generation of Tscm cells. N-acetylcysteine (NAC), the most effective molecule in this regard, induced transcriptional and metabolic programs characteristic of self-renewing memory T cells. Upon ACT, NAC-generated Tscm cells established long-term memory in vivo and exerted more potent antitumor immunity in a xenogeneic model when redirected with CD19-specific CAR, highlighting the translational relevance of NAC as a simple and inexpensive method to improve ACT.
| S-EPMC6237218 | biostudies-literature
Project description:CD8 tissue-resident memory T cells (TRM) provide frontline immunity in mucosal tissues. The mechanisms regulating CD8 TRM maintenance, heterogeneity, protective and pathological functions are largely elusive. Here we identify an epitope-specific CD8 TRM population that is maintained by in situ MHC-I and B7 signaling following acute influenza infection. These TRM cells co-exhibit exhausted-like phenotypes and memory features, and provide heterologous immunity against secondary infection. PD-L1 blockade at the memory stage promotes exhausted-like TRM rejuvenation and secondary immunity at the cost of developing post-infection fibrotic sequelae. Increased numbers of CD8 TRM cells are observed in the lungs of pulmonary fibrosis patients compared to control patients. Thus, TRM exhaustion results from a tissue-specific cellular adaptation to balance fibrotic sequelae and secondary immunity.
2019-03-21 | GSE115786 | 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:During a T cell response, naïve CD8 T cells differentiate into effector cells. Subsequently, a subset of effector cells termed memory precursor effector cells (MPECs) further differentiates into functionally mature memory CD8 T cells. The transcriptional network underlying this carefully scripted process is not well understood. Here, we report that the transcription factor FoxO1 plays an integral role in facilitating effector to memory transition and functional maturation of memory CD4 and CD8 T cells. We find that FoxO1 is not required for differentiation of effector cells, but in the absence of FoxO1, memory CD8 T cells displayed features of scenescence and progressive attrition in polyfunctionality, which in turn led to impared recall responses and poor protective immunity. These data suggest that FoxO1 is essential for active maintenance of functional CD8 T cell memory and protective immunity. Under competing conditions in bone marrow Single-cell suspensions from splenocytes of eight samples WT (control) and FoxO1-/- (experimental) LCMV-immune mice were prepared using standard procedures. CD8 T cells were then isoloated using Thy1.2 (CD90.2) (30-H12) microbeads (Miltenyi Biotec). Cells were then stained with anti-CD8, anti-CD44 and Db/NP396 MHC class I tetramer. Activated (CD8+CD44hi), naive (CD8+CD44lo), and virus-specific CD8 T cells were sorted using FACSAria II instrument (BD Biosciences). The purity of the cells was >95%. Total RNA was extracted from the sorted cells by Trizol Reagent. RNA samples were reverse transcribed and Cy3-labeled cDNAs were hyrbidized to Agilent whole Mouse Genome Oligo Microarrays. Fluorscence signals were detected using Agilent's Microarray Scanner system, data was analyzed using the Rosetta Resolver gene expression data analysis system and genes with a fold change < and p-values <0.01 were identified. Microarray data discussed in the paper is focused on virus-specific memory CD8 T cells from samples WT_Tet_2 vs KO_Tet_2.
2013-06-25 | E-GEOD-45673 | biostudies-arrayexpress
Project description:Memory CD8+ T cells are indispensable for maintaining long-term immunity against intracellular pathogens and tumors. Despite their presence in oxygen-deprived tissues of infection sites or tumors, the impact of local oxygen pressure on memory CD8+ T cells has remained largely unclear. We sought to elucidate how oxygen pressure impacted memory CD8+ T cells arising after infection with Listeria monocytogenes-OVA. Our data revealed that reduced oxygen pressure during in vitro culture switched CD8+ T cell metabolism from an OXPHOS to a glycolytic phenotype. Quantitative proteomic analysis showed that limiting oxygen conditions increased the expression of glucose transporters and components of the glycolytic pathway, while decreasing TCA cycle and mitochondrial respiratory chain proteins. The altered CD8+ T cell metabolism did not affect the expansion potential, but enhanced the granzyme B and IFN- production capacity. Memory CD8+ T cells cultured under low oxygen pressure were able to persist long-term in vivo and provided protection against bacterial rechallenge. Taken together, our study indicates that strategies of cellular immune therapy may benefit from reducing oxygen during culture to develop memory CD8+ T cells with superior effector functions .
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Project description:Here we demonstrate that inactivation of the essential autophagy genes, Atg5, Atg14, or Atg16L1 results in tumour rejection. Despite a significant reduction in the total number of CD8+ tumour infiltrating lymphocytes (TILs), loss of Atg5 causes a profound shift toward IFNg and TNF producing effector memory cells. Consistent with this, adoptive transfer with Atg5-/- T cells promotes tumour control. Mechanistically, CD8+ T cells lacking autophagy exhibit enhanced glucose metabolism resulting in global changes in histone trimethylation and increased transcriptional activation of effector target genes. Restricting glucose is sufficient to suppress autophagy-dependent increases in effector function and reverse alterations in histone trimethylation. These findings identify autophagy as a cell-autonomous negative regulator of CD8+ T cell anti-tumour immunity with implications on T cell-based immunotherapy.
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Project description:CD8 T cells play a crucial role in immunity to infection and cancer. They are maintained in constant numbers, but upon stimulation with antigen undergo a developmental program characterized by distinct phases encompassing the expansion and then contraction of antigen-specific populations, followed by the persistence of long-lived memory cells. Although this predictable pattern of a CD8 T cell response is well established, the underlying cellular mechanisms regulating the transition to memory remain undefined. Here we show that TRAF6, an adapter protein in the TNF-receptor (TNFR) and IL-1R/TLR superfamily, regulates CD8 T cell memory development following infection by modulating fatty acid metabolism. We show that mice with a T cell-specific deletion of TRAF6 mount robust primary CD8 T cell effector responses, but have a profound defect in their ability to generate memory. This defect is CD8 T cell intrinsic and is characterized by the disappearance of antigen-specific cells in the weeks following primary immunization. Microarray analyses revealed that TRAF6-deficient CD8 T cells from early timepoints following immunization exhibit altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lacking TRAF6 are unable to upregulate mitochondrial β-oxidation in response to growth factor withdrawal in vitro. Treatment with drugs that induce fatty acid oxidation enabled CD8 T cell memory generation in the absence of TRAF6. Remarkably, these treatments also increased CD8 T cell memory in wild type mice, and consequently were able to significantly improve the efficacy of an experimental anti-cancer vaccine.
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