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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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T cell receptor dependent transformation of mature memory phenotype T cells

ABSTRACT: A fundamental goal in cancer research is identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth as this has the potential to reveal features that can be exploited therapeutically. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies but are unlikely to underlie initiation of mature lymphoid neoplasms, the cellular origin of which remains unclear. Here, we used a conditional Snf5 model to investigate the origin of peripheral T cell lymphomas. We find that the cell of origin is a mature CD44hiCD122lo CD8 T cell that resembles a subset of memory cells, a population with capacities for self-renewal and robust expansion - features shared with stem cells. We elucidate mechanism by showing that Snf5 loss leads to activation of a Myc network and stem cell transcriptional program. Finally, we demonstrate that lymphomagenesis depends upon TCR signaling, establishing a new paradigm for lymphomagenesis. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells is associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers. Stable mouse Snf5-deficient T cell lymphoma cell lines were established. CD44hi and CD44lo subpopulations were purified and used to evaluate gene expression pattern in these two subpopulations. RNA was isolated from each of these samples and used for gene expression profiling on Affymetrix 430A arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Xi Wang

PROVIDER: E-GEOD-29732 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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T cell receptor dependent transformation of mature memory phenotype T cells

Project description:A fundamental goal in cancer research is identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth as this has the potential to reveal features that can be exploited therapeutically. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies but are unlikely to underlie initiation of mature lymphoid neoplasms, the cellular origin of which remains unclear. Here, we used a conditional Snf5 model to investigate the origin of peripheral T cell lymphomas. We find that the cell of origin is a mature CD44hiCD122lo CD8 T cell that resembles a subset of memory cells, a population with capacities for self-renewal and robust expansion - features shared with stem cells. We elucidate mechanism by showing that Snf5 loss leads to activation of a Myc network and stem cell transcriptional program. Finally, we demonstrate that lymphomagenesis depends upon TCR signaling, establishing a new paradigm for lymphomagenesis. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells is associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers.

2011-11-01 | GSE29732 | GEO

Heterogeneous maintenance of human tissue resident memory T cells based on efflux capacities

Project description:Tissue-resident memory T cells (TRM) accelerate pathogen clearance through rapid and enhanced functional responses in situ. In humans, TRM cells are prevalent in diverse anatomic sites throughout the human lifespan, yet mechanisms for long-term maintenance are unknown. Here, we identify subpopulations of human TRM in mucosal and lymphoid sites based on differential efflux of mitochondrial dyes, with distinct transcriptional profiles, turnover, and functional capacities. TRM are enriched in efflux(+) populations compared with circulating memory CD8+T cells. Compared to efflux- TRM, efflux(+) TRM showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling to homeostatic cytokines. Moreover, efflux(+) and efflux(-) TRM subsets both maintain TRM characteristics when activated, while efflux(+) TRM produce IL-17 and efflux(-) produce higher levels of IFN-γ and IL-2. Our results suggest a model for cooperative maintenance of T cell immunity in tissues through interplay of subsets with complementary capacities for longevity and effector function.

2018-12-26 | GSE109841 | GEO

Resident T Cell Repertoires

Project description:Regulatory T (Treg) are present in lymphoid and non-lymphoid tissues and restrict immune activation, prevent autoimmunity and regulate inflammation. While Treg in non-lymphoid tissues are typically resident, Treg in lymph nodes (LNs) predominantly recirculate and residency of Treg in LNs is poorly studied. Here, we show that 10-20% of all Treg in LNs are memory-like resident cells. Both thymic and peripheral Treg contributed to the pool of resident Treg and their residency did not require continuous TCR signaling. Yet, resident and circulating Treg had distinct TCR repertoires and different LNs contained distinct clonal subpopulations of resident Treg. We speculate that stochastic selection and variation in antigen availability governs commitment of individual T cell clones to the resident pool in each LN. Our results describe a framework for local fine-tuning of immune responses in LNs based on previous adaptive immune responses.

2022-02-04 | GSE195930 | GEO

Human lymph nodes maintain a unique subset of resident memory T cells with high functional potential important for protective immunity and immunotherapies

Project description:Tissue resident memory T cells (TRM) predominate in barrier sites and mediate protective immunity, while their role in lymphoid tissues is undefined. Here we analyzed memory CD8+ T cells in different lymphoid compartments including bone marrow, spleen, and lymph nodes (LN) relative to lung within diverse individuals. We identify an organ-specific subset in human LN (TLN) not found in blood or other tissues, expressing high levels of TCF-1 and transcriptionally enriched for markers of quiescence, self-renewal and follicular-helper cells. High dimensional CyTOF analysis reveals TLN as intermediate in differentiation between naive and TRM cells, with circulating memory T cells the most differentiated. TLN exhibit higher TCR diversity, lower in vivo turnover, yet higher proliferative responses compared to memory cells in other lymphoid or mucosal sites. These findings establish human LN as reservoirs for diverse memory T cells poised for high expansion and TLN as important targets for in vivo immunotherapies.

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Single cell profiling of CD4+ T cells from human fetal intestine

Project description:The fetus is thought to be protected from exposure to foreign antigens, yet CD45RO+ T-cells reside in the fetal intestine. We combined functional assays with mass cytometry, single-cell RNA-sequencing, and high-throughput TCR-sequencing to characterize the fetal intestinal CD4+ T-cell compartment. We identified 22 CD4+ T-cell clusters, including naive-like, regulatory-like, and memory-like subpopulations, which were confirmed and further characterized at the transcriptional level. Memory-like cells expressed high levels of Ki-67, indicating cell division, and CD5, a surrogate marker of TCR-avidity, and produced IFN-γ and IL-2. Pathway analysis revealed a differentiation trajectory associated with cellular activation and proinflammatory effector functions, and TCR-repertoire analysis demonstrated clonal expansions, distinct repertoire characteristics, and interconnections between subpopulations of memory-like CD4+ T-cells. Imaging-mass cytometry further showed that memory-like CD4+ T-cells colocalized with antigen-presenting cells. Collectively, these results provided evidence for the generation of memory-like CD4+ T-cells in the human fetal intestine, consistent with exposure to foreign antigens.

2018-11-24 | GSE122846 | GEO

Resident regulatory T cells reflect the immune history of individual lymph nodes

Project description:Regulatory T cells (Treg) are present in lymphoid and non-lymphoid tissues where they restrict immune activation, prevent autoimmunity and regulate inflammation. Treg in non-lymphoid tissues are typically resident, while those in lymph nodes (LNs) are considered to recirculate. However, Treg in LNs are not a homogenous population and circulation kinetics of different Treg subsets are poorly characterized. Furthermore, whether Treg can acquire memory T cell properties and persist for extended periods after their activation in LNs is unclear. Here, we used in situ labeling with a stabilized photoconvertible protein to uncover turnover rates of Treg in LNs in vivo. We found that while the majority of Treg in LNs recirculate, 10-20% are memory-like resident cells that remain in their respective LNs for weeks to months. Single cell RNA sequencing revealed that LN-resident cells are a functionally and ontogenetically heterogeneous population and share the same core residency gene signature with conventional CD4+ and CD8+ T cells. Resident cells in LNs did not actively proliferate and did not require continuous TCR signaling for their residency. Yet, resident and circulating Treg had distinct TCR repertoires, and each LN contained exclusive clonal subpopulations of resident Treg. Our results demonstrate that, similar to conventional T cells, Treg can form resident memory-like populations in LNs after adaptive immune responses. Specific and local suppression of immune responses by resident Treg in draining LNs might provide new therapeutic opportunities for the treatment of local chronic inflammatory conditions.

2023-08-23 | GSE235702 | GEO

ATAC-seq data from murine peripheral T-cell lymphoma and control normal T cells, NKT cells and NK cells

Project description:Peripheral T-cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcome.T-cell receptor (TCR) is emerging as a key driver of T lymphocytes transformation. However, the role of chronic TCR activation in lymphomagenesis and in survival of lymphoma cells is still poorly understood. Using an original mouse model, we report here that chronic TCR stimulation drives T-cell lymphomagenesis whereas TCR signaling does not contribute to PTCL survival. Epigenetic analyses of mouse PTCLs using ATAC-seq revealed a NK-like reprogramming of PTCL cells with increase accessibility to OCR associated with NK cells.

2021-05-18 | GSE174576 | GEO

Expression data from resting and activated murine T cell as well as murine peripheral T cell lymphomas

Project description:Peripheral T-cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcome.T-cell receptor (TCR) is emerging as a key driver of T lymphocytes transformation. However, the role of chronic TCR activation in lymphomagenesis and in survival of lymphoma cells is still poorly understood. Using an original mouse model, we report here that chronic TCR stimulation drives T-cell lymphomagenesis whereas TCR signaling does not contribute to PTCL survival. Transcriptome analyses of mouse PTCLs revealed a NK-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and Syk.

2021-05-11 | GSE174257 | GEO

Expression data from Human CD4 T cells subpopulations of HIV+ patients and HIV- controls

Project description:Central memory CD4 T cells (TCM) have a critical homeostatic role in chronic HIV infection. We asked if TCM cells from HIV+ patients have a gene expression profile related with less proliferation and less survival capacities. To determine the gene expression profile of CD4+ T cells subpopulations we performed microarrays (Human Gene 1.0 ST, Affymetrix) to identify differentially expressed genes between CD4+ T cells subpopulations from HIV+ patients and controls.

2016-11-25 | GSE73968 | GEO

Expression data from virus-specific mouse Th1 and Tfh CD4 T cell subsets after LCMV infection

Project description:CD4 T follicular helper (Tfh) cells provide the required signals to B cells for germinal center reactions that are necessary for longlived antibody responses. However, it remains unclear whether there are CD4+ memory T cells committed to the Tfh lineage after antigen clearance. Using adoptive transfer of antigen-specific memory CD4+ subpopulations (based on CXCR5 and Ly6c expression)in the LCMV infection model, we found that there are distinct memory CD4+ T cell populations with commitment to the Tfh and Th1 lineages. Our conclusions are based on gene expression profiles, epigenetic studies and phenotypic and functional analysis. The gene expression profiles of virus-specific CD4 T cell subets at effector and memory stages is presented here. The SMARTA TCR transgenic / adptive transfer system was used to identify and sort subsets of antigen-specific CD4 T cells (based on their expression of Ly6c and CXCR5) elicited after acute infection with LCMV (Arm).

2013-04-22 | E-GEOD-43863 | biostudies-arrayexpress

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