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A distinct CD8+ T cell subset derived from virtual memory T cells causes alopecia areata through innate-like cytotoxicity [scRNA-seq]

ABSTRACT: Virtual memory T (TVM) cells are a T-cell subtype that exhibit a memory phenotype without prior exposure to a foreign antigen. Although several recent studies suggest that TVM cells exert anti-viral and anti-bacterial function, pathological roles of TVM cells causing inflammatory diseases have not been studied. Here, we identified a novel CD8+ T-cell subset (CD44s-hiCD49dlo CD8+ T cells), which is originated from TVM cells and can cause a chronic inflammatory disease, alopecia areata (AA). In the skin of alopecic mice, we detected a distinct TVM-cell subpopulation characterized by superior expression of CD44 and features of tissue residency, which was transcriptionally, phenotypically, and functionally distinct from conventional CD8+ TVM cells. Mechanistically, this cell population could be induced from conventional TVM cells by IL-12, IL-15, and IL-18 stimulation. Moreover, the pathological activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-depedent innate-like cytotoxicity against target cells, which was further augmented by IL-15 stimulation and triggered the onset of disease. Collectively, our results suggest a new immunological mechanism through which TVM cells can cause chronic inflammatory disease by innate-like cytotoxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE229581 | GEO | 2023/05/16

REPOSITORIES: GEO

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A distinct CD8+ T cell subset derived from virtual memory T cells causes alopecia areata through innate-like cytotoxicity [RNA-seq]

Project description:Virtual memory T (TVM) cells are a T-cell subtype that exhibit a memory phenotype without prior exposure to a foreign antigen. Although several recent studies suggest that TVM cells exert anti-viral and anti-bacterial function, pathological roles of TVM cells causing inflammatory diseases have not been studied. Here, we identified a novel CD8+ T-cell subset (CD44s-hiCD49dlo CD8+ T cells), which is originated from TVM cells and can cause a chronic inflammatory disease, alopecia areata (AA). In the skin of alopecic mice, we detected a distinct TVM-cell subpopulation characterized by superior expression of CD44 and features of tissue residency, which was transcriptionally, phenotypically, and functionally distinct from conventional CD8+ TVM cells. Mechanistically, this cell population could be induced from conventional TVM cells by IL-12, IL-15, and IL-18 stimulation. Moreover, the pathological activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-depedent innate-like cytotoxicity against target cells, which was further augmented by IL-15 stimulation and triggered the onset of disease. Collectively, our results suggest a new immunological mechanism through which TVM cells can cause chronic inflammatory disease by innate-like cytotoxicity.

2023-05-16 | GSE229145 | GEO

Comparison of young and aged mouse CD8 TN, TVM and TMEM cells directly ex vivo and after polyclonal stimulation

Project description:The overall study (Quinn et al. Cell Reports, 2018) aimed to understand why CD8 virtual memory T (TVM) cells become markedly less proliferative in response to TCR-driven signals with increasing age, whereas CD8 true naive (TN) cells maintain their proliferative capacity. Age-associated decreases in primary CD8+ T cell responses occur, in part, due to direct effects on naïve CD8++ T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Ageing also causes accumulation of antigen-naïve but semi-differentiated “virtual memory” (TVM) cells but their contribution to age-related functional decline is unclear. Here, we show that TVM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naïve T cells (TN cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naïve CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged TVM cells exhibit a profile consistent with senescence, marking the first description of senescence in an antigenically naïve T cell population.

2018-06-19 | GSE112304 | GEO

Identification of a glycosphingolipid+ immune regulatory innate-like CD8 T-cell network in old mice

Project description:The reciprocal decline in naive (TN) and increase in virtual (TVM) and true memory (TTM) CD8 T-cell frequencies upon aging is incompletely understood. We established the glycosphingolipid asialo-GM1 (AsGM1) marker present on >70% of TVM/TTM and 5-15% TN to target their immune-regulatory and homeostatic potential. We identified a novel AsGM1+ old CD8 TN-subset that was related to antigen-experienced AsGM1+ CD8 TTM and showed an initial immune-regulatory (Pdcd1, Il10) gene expression signature. The program for AsGM1+ CD8 T-subsets was imprinted genetically in young and old hematopoietic stem cells that reconstitute young and old donor-type immune systems in lymphophenic RAG1-/- mice within 16 weeks, respectively. However, antibody-mediated depletion of AsGM1+ T cells in old mice revealed a disturbed recovery of CD8 TVM resulting in a rejuvenated T-subset composition and T-cell priming capacity upon DNA-vaccination. Old CD8 TVM and IL10+ PD-1+ TTM exerted immune-regulatory functions and suppressed CD3/CD28-mediated activation of TN in vitro. Glycosphingolipids thus are attractive to identify and target novel T-subsets.

2023-05-22 | GSE210352 | GEO

Virtual memory T-cells orchestrate extra-lymphoid responses conducive to resident memory

Project description:A primary immune response is typically initiated in secondary lymphoid organs. Virtual memory CD8+ T (TVM) cells are antigen-inexperienced T cells of a central-memory phenotype, acquired through self antigen-driven homeostatic proliferation. Unexpectedly, here we find that, TVM cells are composed of CCR2+ and CCR2- subsets that differentially elaborate a spectrum of effector- and memory-poised functions directly in the tissue. During a primary flu infection, TVM cells rapidly infiltrate the lung in the first day and execute early viral control. TVM cells that recognize viral antigen are retained in the tissue, clonally expand independent of secondary lymphoid organs, and preferentially give rise to tissue-resident memory cells. By orchestrating an extra-lymphoid primary response, heterogenous TVM cells bridge innate reaction and adaptive memory directly in the infected tissue.

2021-06-15 | GSE148364 | GEO

Expression data from naive and memory CD8 T cells cultured in presence or absence of IL-4

Project description:Effects of IL-4 on CD8 T cells functions are largely unknown. IL-4 induces survival and proliferation of CD8 T cells, but several studies suggest that IL-4 could also affect several functions of CD8 T cells such as cytotoxicity. Our team has shown that IL-4 repress the expression of Ccl5 in vitro. To define more precisely the impact of IL-4 on CD8 T cells, we performed a whole genome expression microarray analysis of naive and memory CD8 T cells cultured in presence or absence of IL-4. This approach allowed us to define the IL4-gene-expression signature on CD8 T cells. 18 samples were processed. Two populations of F5 naive CD8 T cells were FACS-sorted: samples from each population were incubated 20 hours with IL-7 in presence or absence of IL-4. Thus, a total of 6 “Naive” samples were processed. In addition, 4 populations of F5 TIM memory CD8 T cells were FACS-sorted: samples from 2 of these populations were incubated 20 hours in presence of IL-7 and/or IL-4, or in medium alone. Thus, 12 “Memory” samples were processed.

2011-09-27 | E-GEOD-32423 | biostudies-arrayexpress

Runx3 function in IL-2-activated splenic CD8+ T cells

Project description:CD8+T cells are immune cells that recognize foreign antigens on infected and tumor cells, leading to cytokine-dependent expansion and activation of cytotoxicity towards the targets. To identify Runx3 regulated genes, CD8+ T cells were isolated from spleen of WT and Runx3-/- mice . Six samples (3 WT and 3 Runx3-/-) of CD8+ T cells were separately obtained from individual mice, TCR activated and cultured for 4 days with IL-2.

2013-11-18 | E-GEOD-50121 | biostudies-arrayexpress

Expression data from naive and memory CD8 T cells cultured in presence or absence of IL-4

2011-09-28 | GSE32423 | GEO

Transcription profiling by array of decidual CD8+ CCR7-CD45RA- Effector-Memory T cells

Project description:To understand the regulation of cytotoxicity by decidual CD8+ T cells (CD8+ dT) at the maternal-fetal interface, gene expression analysis of CCR7-CD45RA- effector-memory CD8+ T cells isolated from peripheral blood of unrelated healthy controls and decidual tissue from first trimester (6-12 weeks) and term (>37 weeks) pregnancy was performed. Furthermore, first trimester decidual effector-memory CD8+ T cells were stimulated with anti-CD3/CD28 in the presence of IL-2 for 12 hours or 72 hours. RNA was isolated and gene expression profiles were generated by employing Affymetrix HG_U133_Plus 2 arrays on the Affymetrix Geneatlas system.

2017-12-19 | E-MTAB-5890 | biostudies-arrayexpress

IL-12 signaling contributes to the reprogramming of neonatal CD8+ T cells

Project description:Neonates are highly susceptible to intracellular pathogens, leading to high morbidity and mortality rates. CD8+ T lymphocytes are responsible for the elimination of infected cells. Understanding the response of these cells to normal and high stimulatory conditions is important to propose better treatments for neonates. We have previously shown that human neonatal CD8+ T cells overexpress innate inflammatory genes and have a low expression of cytotoxic and cell signaling genes. To investigate the activation potential of these cells, we evaluated the transcriptome of human neonatal and adult naïve CD8+ T cells after TCR/CD28 signals +/- IL-12. We found that in neonatal cells, IL-12 signals contribute to the adult-like expression of genes associated with cell-signaling, T-cell cytokines, metabolism and cell division. Additionally, IL-12 signals contributed to the downregulation of the neutrophil signature transcription factor CEBPE and other immaturity related genes. To validate the transcriptome results, we evaluated the expression of a series of genes by RT-qPCR and the promoter methylation status on independent samples. We found that, in agreement with the transcriptome, IL-12 signals induced both the chromatin closure of neutrophil-like genes and the opening of cytotoxicity genes, suggesting that IL-12 signals contribute to the epigenetic reprogramming of neonatal lymphocytes. Furthermore, a high expression of some inflammatory genes was observed in naive and stimulated neonatal cells, in agreement with the high inflammatory profile of neonates to infections. Altogether our results point to an important contribution of IL-12 signals to the reprogramming of the neonatal CD8+ T cells.

2020-05-25 | GSE144108 | GEO

Expression data from IL-10+ and IL-10- CD8 T cells

Project description:IL-10 is an anti-inflammatory cytokine that has been shown to be produced by antigen-specific CD8 T cells at the peak of viral encephalitis. We found that IL-10+CD8 T cells are more activated and cytolytic than IL-10-CD8 T cells. We used microarrays to detect gene expression changes in directly ex vivo sorted CNS IL-10+ and IL-10- CD8 T cells from a neurotropic J2.2-V-1-infected mouse. C57Bl/6 Vert-X (IL-10-eGFP) mice were infected intracranially with 500 PFU J2.2-V-1 virus and seven days later their brain lymphocytes from three mice were pooled and then isolated and negatively selected for CD8 T cells. The CD8 pooled brain lymphocytes were then sorted for IL-10+ and IL-10- CD8 T lymphocytes using GFP as a marker from the same samples. This was performed three times to obtain six samples total. RNA was extracted and hybridized to GeneChip Mouse GENE 1.0 ST arrays (Affymetrix).

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