Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE79774 | GEO | 2016/10/23
SECONDARY ACCESSION(S): PRJNA316986
REPOSITORIES: GEO
Similar Datasets
Project description:A specialized population of memory CD8+ T-cells resides in the epithelium of the respiratory tract to maintain protection against recurring infections. These cells express CD69 and the integrin αβ7 (CD103) and correspond to tissue resident memory T-cells (TRM) also described in intestine, liver and brain. A less well characterized population of CD103- CD8+ T-cells also resides in lungs and expresses markers characteristic of effector memory T-cells (TEM). We determined the transcriptional profiles of these memory CD8+ T-cell subsets retrieved from human lung resection samples and compared these with corresponding T-cell populations from peripheral blood of the same individuals. Our results demonstrate that each of the populations exhibits a distinct transcriptional identity. We found that the lung environment has a major impact on gene expression profiles. Thus, transcriptomes from CD103+ and CD103- subsets from lungs are much more resemblant to one another than to those from CD103+ or CD103- memory CD8+ T-cells from blood. TRM express specific sets of chemokine receptors, in accordance with their unique migratory properties. Furthermore, these cells constitutively express cytokine and cytotoxic genes for immediate effector function and chemokines to attract auxiliary immune cells. At the same time, multiple genes encoding inhibitory regulators are also expressed. This suggests that rapid ability to unleash effector functions is counterbalanced by programmed restraint, a combination that may be critical in the exposed but delicate tissue of the lung. Comprehensive sets of transcription factors were identified that characterize the memory CD8+ populations in the lungs. Prominent among these were components of the Notch pathway. Using mice genetically lacking expression of the NOTCH1 and NOTCH2 receptors in T-cells, we demonstrated that Notch controls both the number of lung TRM as well as the function of lung TEM. Our data illustrate the adaptation of lung resident T-cells to the requirements of the respiratory epithelial environment. Defining the molecular imprinting of these cells is important for rational vaccine design and may help to improve the properties of T-cells for adoptive cellular therapy. Material was collected from a total of 6 subjects. Three patients underwent a lobectomy for a peripheral primary lung tumor and three received lung transplantation because of end-stage pulmonary disease (COPD). Lung mononuclear cells where isolated after digestion of the partial or complete human lung resection material. Paired peripheral blood mononuclear cells were also isolated. CD8+CD16-CD56- T-cells were sorted for expression of CD103 (ITGAE). Lung and blood derived CD103+ and CD103- T-cell fractions were directly lysed after FACS sorting or stimulated overnight with antiCD3/28 beads. Due to the low frequency of resting (non-stimulated) CD103+ T-cells in peripheral blood this subset was obtained from five non-related buffy coat donors. RNA was isolated from 36 sorted cell samples and hybridized on Illumina HumanHT-12 V4.0 microarrays. Eight microarray samples (including two samples from the buffy coat donors) were excluded after hybridization since their average signal was too low.
2016-10-23 | E-GEOD-61397 | biostudies-arrayexpress
Project description:A specialized population of memory CD8+ T-cells resides in the epithelium of the respiratory tract to maintain protection against recurring infections. These cells express CD69 and the integrin αβ7 (CD103) and correspond to tissue resident memory T-cells (TRM) also described in intestine, liver and brain. A less well characterized population of CD103- CD8+ T-cells also resides in lungs and expresses markers characteristic of effector memory T-cells (TEM). We determined the transcriptional profiles of these memory CD8+ T-cell subsets retrieved from human lung resection samples and compared these with corresponding T-cell populations from peripheral blood of the same individuals. Our results demonstrate that each of the populations exhibits a distinct transcriptional identity. We found that the lung environment has a major impact on gene expression profiles. Thus, transcriptomes from CD103+ and CD103- subsets from lungs are much more resemblant to one another than to those from CD103+ or CD103- memory CD8+ T-cells from blood. TRM express specific sets of chemokine receptors, in accordance with their unique migratory properties. Furthermore, these cells constitutively express cytokine and cytotoxic genes for immediate effector function and chemokines to attract auxiliary immune cells. At the same time, multiple genes encoding inhibitory regulators are also expressed. This suggests that rapid ability to unleash effector functions is counterbalanced by programmed restraint, a combination that may be critical in the exposed but delicate tissue of the lung. Comprehensive sets of transcription factors were identified that characterize the memory CD8+ populations in the lungs. Prominent among these were components of the Notch pathway. Using mice genetically lacking expression of the NOTCH1 and NOTCH2 receptors in T-cells, we demonstrated that Notch controls both the number of lung TRM as well as the function of lung TEM. Our data illustrate the adaptation of lung resident T-cells to the requirements of the respiratory epithelial environment. Defining the molecular imprinting of these cells is important for rational vaccine design and may help to improve the properties of T-cells for adoptive cellular therapy.
2016-10-23 | GSE61397 | GEO
Project description:Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation.
2020-09-01 | GSE137386 | GEO
Project description:Tissue-resident memory T (TRM) cells are crucial mediators of adaptive immunity in non-lymphoid tissues. However, the functional heterogeneity and pathogenic roles of CD4+ TRM cells that reside within chronic inflammatory lesions remain unknown. We found that CD69hiCD103low CD4+ TRM cells produced effector cytokines and promoted the inflammation and fibrotic responses induced by chronic exposure to Aspergillus fumigatus. Simultaneously, immunosuppressive CD69hiCD103hiFoxp3+ CD4+ regulatory T (Treg) cells were induced and constrained the ability of pathogenic CD103low TRM cells to cause fibrosis. Thus, lung tissue-resident CD4+ T cells play crucial roles in the pathology of chronic lung inflammation, and CD103 expression defines pathogenic effector and immunosuppressive tissue-resident cell subpopulations in the inflamed lung.
2020-06-30 | GSE133399 | GEO
Project description:Lung resident memory (Trm) CD8 T cells induced by influenza A virus (IAV), are pivotal for providing heterosubtypic immunity, but are not maintained long term, causing gradual loss of protection. This contrasts sharply with long-term maintenance of Trm induced by localized infections of the skin and other tissues. Here we show that the decline in lung Trm is determined by an imbalance between apoptosis and lung recruitment/conversion to Trm of circulating memory cells. At the cellular level, circulating effector memory (Tem) rather than central memory (Tcm) cells are the precursors for conversion to lung Trm. Time-dependent changes in expression of genes critical for Trm differentiation together with enrichment of Tcm diminish the capacity of circulating memory CD8 T cells to form Trm, explaining why IAV-induced Trm are not stably maintained over time. Importantly, systemic booster immunization, through increasing the number of circulating Tem cells, induces an increase in lung Trm pool, providing a new rational for future IAV vaccines.
2016-11-18 | GSE86973 | GEO
Project description:Previous pneumococcal experience establishes lung-resident IL-17A-producing CD4+ memory TRM cells that accelerate neutrophil recruitment against heterotypic pneumococci. Herein, we unravel a novel crosstalk between CD4+ TRM cells and lung epithelial cells underlying this protective immunity. Genome-wide expression analyses of lung epithelial cells in CD4+ cell sufficient and CD4+ cell deficient heterotypic immune murine lungs revealed a significant remodeling of the epithelial transcriptome of infected lungs due to infection history, ~80% of which was CD4+ cell-dependent.
2020-03-16 | GSE128897 | GEO
Project description:Tissue-resident memory CD8+T (TRM) cells are a distinct component of the memory T cell armamentarium found in many tissues. Recent studies have shown disparities among TRM cells across tissues, but it is unknown whether there is heterogeneity among TRM cells from differentanatomic compartments of the small intestine and colon. Herewe show that intestinal TRM cells exhibit distinctive patterns of cytokine and granzyme expression, along with substantial transcriptional, epigenetic, and functional heterogeneity. We elucidate unexpected tissue- and context-specific regulatory roles for the T-box transcription factor Eomesodermin (Eomes), previously described to repressskin, liver, and kidney TRM cell formation, in promoting the maintenance of established TRM cells in the small intestine, but not in the colon. Taken together, these data provide previously unappreciated insights into the heterogeneity and differential requirements for the formation vs. maintenance of TRMcells from the small intestine and colon.
2022-12-28 | GSE205941 | GEO
Project description:Tissue-resident memory CD8+T (TRM) cells are a distinct component of the memory T cell armamentarium found in many tissues. Recent studies have shown disparities among TRM cells across tissues, but it is unknown whether there is heterogeneity among TRM cells from differentanatomic compartments of the small intestine and colon. Herewe show that intestinal TRM cells exhibit distinctive patterns of cytokine and granzyme expression, along with substantial transcriptional, epigenetic, and functional heterogeneity. We elucidate unexpected tissue- and context-specific regulatory roles for the T-box transcription factor Eomesodermin (Eomes), previously described to repressskin, liver, and kidney TRM cell formation, in promoting the maintenance of established TRM cells in the small intestine, but not in the colon. Taken together, these data provide previously unappreciated insights into the heterogeneity and differential requirements for the formation vs. maintenance of TRMcells from the small intestine and colon.
2022-12-28 | GSE205549 | GEO
Project description:Tissue-resident memory CD8+ T cells (TRM) constitute a non-circulating memory T cell subset that provides early protection against re-infection. However, how TRM arise from antigen-triggered T cells has remained unclear. Exploiting the TRM-restricted expression of Hobit, we developed TRM reporter/deleter mice to study TRM differentiation. We found that Hobit was upregulated in a subset of LCMV-specific T cells located within peripheral tissues during the effector phase of the immune response. These Hobit+ effector T cells were identified as TRM precursors, given that their depletion substantially decreased TRM development, but not the formation of circulating memory T cells. Adoptive transfer experiments of Hobit+ effector T cells corroborated their biased contribution to the TRM lineage. Transcriptional profiling of Hobit+ effector T cells underlined the early establishment of TRM properties including downregulation of tissue exit receptors and upregulation of TRM-associated molecules. Importantly, we identified Eomes as a key factor instructing the early bifurcation of circulating and resident lineages. These findings establish that commitment of TRM occurs early in antigen-driven T cell differentiation and reveal the molecular mechanisms underlying this differentiation pathway.
2021-08-19 | GSE182343 | GEO
Project description:Tissue resident memory T cells (TRM) maintain immunity in diverse sites as determined in mouse models, while their establishment and role in human tissues has been difficult to assess. Here, we investigated human lung TRM generation, maintenance and function in airway samples obtained longitudinally from HLA-disparate lung transplant recipients, where donor and recipient T cells could be localized and tracked over time. Donor T cells persist specifically in the lungs (and not blood) of transplant recipients and express high levels of TRM signature markers including CD69, CD103, and CD49a, while lung-infiltrating recipient T cells gradually acquire TRM phenotypes over months in vivo. Single cell transcriptome profiling of airway T cells reveals that donor T cells comprise two TRM-like subsets with varying levels of expression of TRM-associated genes while recipient T cells comprised non-TRM and similar TRM-like subpopulations, suggesting de novo TRM generation. Transplant recipients exhibiting higher frequencies of persisting donor TRM experienced fewer adverse clinical events such as primary graft dysfunction and acute cellular rejection compared to recipients with low donor TRM persistence, suggesting that monitoring TRM dynamics could be clinically informative. Together, our results provide novel spatial and temporal insights into how human TRM develop, function, persist, and impact tissue integrity within the complexities of lung transplantation.
2019-04-03 | GSE124675 | GEO