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Transcriptome profile of memory phenotype CD8 T cells are shaped by overexpression of CD103

ABSTRACT: The CD8 T cells in the peripheral tissues maintained as a mixture of naïve and memory-phenotype in the steady state, while the mechanism how the balance of naïve and memory-phenotype CD8 T cells is controlled remains unclear. Here, we report that integrin CD103 plays critical role in this process. CD103 is differentially expressed on peripheral CD8 T cells with highest expression on naïve CD8 T cells (Ly6C–CXCR3–) and lowest expression on memory-phenotype CD8 T cells (Ly6C+CXCR3+). To understand the biological significance of CD103 downregulation on memory-phenotype CD8 T cells, we generated transgenic mice that overexpress CD103 under the control of the human CD2 promoter/enhancer so that CD103 is constitutively expressed on all T lineage cells (CD103Tg), and we found that memory-phenotype CD8 T cells are accumulated in CD103Tg mice. Therefore, we performed RNA sequencing on sorted memory-phenotype CD8 T cells from WT and CD103Tg mice to elucidate the molecular mechanism how forced expression of CD103 promotes accumulation of memory-phenotype CD8 T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE295529 | GEO | 2025/09/24

REPOSITORIES: GEO

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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 Î±Î²7 (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.

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Transcriptome profile of memory phenotype CD8 T cells are shaped by overexpression of CD103

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