Dataset Information

Identification of different human CD8 T cell subsets by superior cytotoxicity in human T cells

ABSTRACT: Cytotoxic CD8+ T cells can effectively kill target cells by producing cytokines, chemokines and granzymes. Expression of these effector molecules is however highly divergent, and tools that identify and pre-select potent killer cells are lacking. Human CD8+ T cells can be divided into IFNGand IL-2 producing cells. Unbiased RNA-sequencing and proteomics analysis on cytokine-producing fixed CD8+ T cells revealed that IL-2+ T cells produce helper cytokines, and that IFNG+ T cells produce cytotoxic molecules. IFNG+ cytotoxic T cells expressed the surface marker CD29 already prior to stimulation. CD29 also marked T cells with cytotoxic gene expression from different tissues in single-cell RNA-sequencing data. Notably, the cytotoxic features of CD29+ T cells were maintained during cell culture, suggesting a stable phenotype. Pre-selecting CD29-expressing MART1 TCR-engineered T cells potentiated the killing of target cells. We therefore propose that selecting for CD29+ T cells could boost the anti-tumoral activity of T cell therapeutics.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Blood

SUBMITTER: Maartje van den Biggelaar

LAB HEAD: Maartje van den Biggelaar

PROVIDER: PXD012874 | Pride | 2021-09-08

REPOSITORIES: Pride

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CD29 identifies IFN-γ-producing human CD8+ T cells with an increased cytotoxic potential.

Nicolet Benoît P BP Guislain Aurélie A van Alphen Floris P J FPJ Gomez-Eerland Raquel R Schumacher Ton N M TNM van den Biggelaar Maartje M Wolkers Monika C MC

Proceedings of the National Academy of Sciences of the United States of America 20200311 12

Cytotoxic CD8+ T cells can effectively kill target cells by producing cytokines, chemokines, and granzymes. Expression of these effector molecules is however highly divergent, and tools that identify and preselect CD8+ T cells with a cytotoxic expression profile are lacking. Human CD8+ T cells can be divided into IFN-γ- and IL-2-producing cells. Unbiased transcriptomics and proteomics analysis on cytokine-producing fixed CD8+ T cells revealed that IL-2 ...[more]

PMID: 32161126

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Project description:A recently identified unconventional T cell population known as mucosal-associated invariant T (MAIT) cells are characterized by the expression of semi-invariant T cell receptor (TCR) with a canonical TRAV1-2/TRAJ33 (Vα7.2/Jα33). These evolutionary conserved, innate-like T cells recognize vitamin B metabolites, derived from some bacteria and fungi. Due to their presence not only in the T cell repertoire of mucosal surfaces but also in peripheral blood and liver, and their significant involvement in a wide range of diseases, in-depth characterization of human MAIT cells is a timely requirement. Studies that examined the transcriptome, immunoproteome, and whole-cell proteome characterized the role of cytotoxic molecules and cytokines in effector functions of MAIT cells and their relationship with some other immune cell subsets. As MAIT cells are classified under the CD3+ T cell compartment and the majority express surface receptor CD8, identifying their proteomic relationship with CD3+ and CD8+ T cells is pivotal. Thus, a high-resolution dataset was generated using the cell populations sorted from peripheral blood mononuclear cells of three healthy volunteers to describe the whole cell proteomes of MAIT, CD3+, and CD8+ T cells. Trypsin-digested peptide samples obtained from the methanol co-precipitation method were analyzed using an Orbitrap FusionTM TribridTM mass spectrometer (Thermo Fisher Scientific, USA) inline coupled to nanoACQUITY ultra-performance liquid chromatography system (Waters, USA) to acquire data-dependent shotgun proteomic data (DDA-MS) for label-free quantification. Analysis of raw DDA-MS data using MaxQuant software and maxLFQ identified and quantified 4,442 protein groups at a 1% false discovery rate. Further analysis identified 3,680 proteins which were detected with a single UniProt accession and a minimum of 2 unique or razor peptides. Thus this proteomic dataset can be used as a reference proteome for future studies on human MAIT cells.

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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Dataset Information

Identification of different human CD8 T cell subsets by superior cytotoxicity in human T cells

Dataset's files

Publications

CD29 identifies IFN-γ-producing human CD8<sup>+</sup> T cells with an increased cytotoxic potential.

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