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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE210352 | GEO | 2023/05/22

REPOSITORIES: GEO

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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

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

Antigen-specific CD8 T cells against SARS-CoV-2

Project description:In this project, we characterized the antigen-specific CD8 T cells of people from five groups. We used HLA:A2 tetramers loaded with the GILGFVFTL (Influenza) or YLQPRTFLL (Sars-CoV-2) peptides to label cells. Cells were sorted based on CD3+CD8+TTM+. We distinguished between four groups: 1. SARS2-TTM+ cells 6 months after infection, 2. SARS2-TTM+ cells 1 motnhs after 2nd vaccination with the Pfizer vaccine, 3. SARS2-TTM+ cells of people that were both infected and vaccinated and 4. FLU-TTM+ cells. Cells were sorted and analyzed by bulk RNA sequencing.

2023-04-09 | GSE202262 | GEO

A distinct CD8+ T cell subset derived from virtual memory T cells causes alopecia areata through innate-like cytotoxicity [scRNA-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 | GSE229581 | GEO

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

2023-05-16 | GSE229145 | GEO

Project description:Define,(a) intrinsic differences and (b) changes occuring upon TCR activation in genetic profiles of naive CD4+ and CD8+ T cells from young and old animals, to identify candidate genes altered in old T cells involved in impairement of immune response in order to restore immune function in the old. Activation dependant time series on sorted naive (CD62Lhi/CD44lo) CD4 and CD8 T cells from young and old animals-Each time point contains RNA pooled from 4 independent sortings

2011-03-24 | E-GEOD-28165 | biostudies-arrayexpress

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

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

| PRJNA445598 | ENA

Expression analysis of human naÃ¯ve and memory CD8 T cells at resting stage and following short-term stimulation

Project description:Memory T cells (TM) play a prominent role in protection and auto-immunity due to their ability to mount a more effective response than naÃ¯ve T cells (TN). However, the molecular mechanisms underlying enhanced functionality of TM are not well defined, particularly in human TM. We examined the global gene expression profiles of human CD8+ TN and TM before and after stimulation. There were 1,284, 1,373 and 1,629 differentially expressed genes between TN and TM at 0 hr, 4 hr and 24 hr after stimulation, respectively, with more genes expressed to higher levels in TM. Genes rapidly up-regulated in TN cells were largely involved in nitrogen, nucleoside and amino acid metabolisms. In contrast, those in CD8+ TM were significantly enriched for immune-response-associated processes, including cytokine production, lymphocyte activation and chemotaxis. Multiple cytokines were rapidly up-regulated in TM cells, including effector cytokines known to be produced by CD8+ T cells and important for their functions, as well as regulatory cytokines, both pro- and anti-inflammatory, that are not typically produced by CD8+ T cells. These results provide new insights into molecular mechanisms that contribute to the enhanced functionality of human CD8+ TM and their prominent role in protection and auto-immunity. NaÃ¯ve and memory phenotype CD8 T cells were purified by FACS from healthy individuals and cultured in vitro with the stimulation of anti-CD3/CD28 mAbs for 0 hr, 4 hr and 24 hr. Total RNA was purified from un-stimulated and stimulated naive and memory CD8 T cells and hybridized to individual single-color arrays.The purification and stimulation protocol was performed two independent times.

2016-04-01 | E-GEOD-79828 | biostudies-arrayexpress

scRNA-seq analysis of mouse splenic CD8 T cells 1 month post transfer of CD8 T cells from 3 months old donor into 24 months old recipient

Project description:Aging is associated with systemic chronic inflammation (inflammaging) that leads to impaired physiological functions and vulnerability to several diseases. However, underlying alterations in aged immune system resulting in gradual loss of immune fitness remain unclear. Using a combination of CD8 T cell transfer from young to old and from old to young mice and single-cell RNA sequencing, we characterized the age-associated alterations in CD8 T cells. We transferred 2 millions of purified CD8+ T cells pooled from 3 CD45.1 C57BL/6J 3 months old female mice (donor) by i.v. injection into CD45.2 C57BL/6J 24 months old female mouse (recipient) and sorted CD45.1+CD3e+CD8a+ and CD45.2+CD3e+CD8a+ T cells from the spleen 1 month post transfer to perform scRNA/TCR-seq.

2020-12-06 | GSE155005 | GEO

2011-03-25 | GSE28165 | GEO

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