Cognate antigen-independent differentiation of resident memory t cells in chronic kidney disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1034630 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26632696_1.fastq.gz | Fastqsanger.gz | |||
| SRR26632696_2.fastq.gz | Fastqsanger.gz | |||
| SRR26632697_1.fastq.gz | Fastqsanger.gz | |||
| SRR26632697_2.fastq.gz | Fastqsanger.gz | |||
| SRR26632698_1.fastq.gz | Fastqsanger.gz |
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Project description:Although resident memory T cells (TRMs), which are memory T cells that are retained locally within tissues, have recently been described as antigen-specific frontline defenders against pathogens in barrier and non-barrier epithelial tissues, they have also been noted for perpetuating chronic inflammation. Furthermore, the conditions responsible for TRM differentiation are still poorly understood, and their contributions, if any, to sterile models of chronic kidney disease (CKD) remain a mystery. In this study we identify a substantial population of TRMs in the kidneys of mice with aristolochic acid (AA)-induced CKD. Flow cytometry of injured kidneys showed T cells bearing TRM surface markers and single cell RNA sequencing revealed these cells as expressing well-known TRM transcription factors and receptors responsible for TRM differentiation and maintenance. While kidney TRMs expressed Cd44, a marker of antigen experience and T cell activation, their derivation was surprisingly independent of cognate antigen-T cell receptor interactions, as the kidneys of transgenic OT-1 mice still harbored considerable proportions of TRMs after injury. Our results suggest a non-antigen-specific or antigen-independent mechanism capable of generating TRMs in the kidney and highlight the need to better understand TRMs and their involvement in CKD.
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Project description:CD8+ T cells are a key weapon in the therapeutic armamentarium against cancer. While CD8+CD103+ T cells with a tissue-resident memory T (TRM) cell phenotype associate with favourable prognoses, the tumour microenvironment also contains dysfunctional exhausted T (TEX) cells that exhibit a myriad of TRM-like features. Here, we deconvolute TRM and TEX cells across human cancers, ascribing markers and gene signatures that distinguish these populations and enable their functional distinction. While TRM cells exhibit superior functionality and are associated with long-term survival post-tumour resection, they are not associated with responsiveness to immune checkpoint blockade. Tumour-associated TEX and TRM cells are clonally distinct, with the latter comprising tumour-independent bystanders and tumour-specific cells segregated from cognate antigen. Intratumoural TRM cells can be forced towards an exhausted fate when chronic antigen stimulation occurs, arguing that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between tumour-associated TEX and TRM populations. These results suggest unique roles for TRM and TEX cells in tumour control, underscoring the need for distinct strategies to harness these populations in novel cancer therapies.
2025-10-02 | GSE309625 | GEO
Project description:CD8+ T cells are a key weapon in the therapeutic armamentarium against cancer. While CD8+CD103+ T cells with a tissue-resident memory T (TRM) cell phenotype associate with favourable prognoses, the tumour microenvironment also contains dysfunctional exhausted T (TEX) cells that exhibit a myriad of TRM-like features. Here, we deconvolute TRM and TEX cells across human cancers, ascribing markers and gene signatures that distinguish these populations and enable their functional distinction. While TRM cells exhibit superior functionality and are associated with long-term survival post-tumour resection, they are not associated with responsiveness to immune checkpoint blockade. Tumour-associated TEX and TRM cells are clonally distinct, with the latter comprising tumour-independent bystanders and tumour-specific cells segregated from cognate antigen. Intratumoural TRM cells can be forced towards an exhausted fate when chronic antigen stimulation occurs, arguing that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between tumour-associated TEX and TRM populations. These results suggest unique roles for TRM and TEX cells in tumour control, underscoring the need for distinct strategies to harness these populations in novel cancer therapies.
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Project description:Tissue resident memory T cells (TRM) contained at sites of previous infection provide local protection against re-infection. Whether they form and function in organ transplants where cognate antigen persists is unclear. This is a key question in transplantation as T cells are detected long-term in allografts, but it is not known whether they are exhausted or are functional memory T cells. Using a mouse model of kidney transplantation, we showed that antigen-specific and polyclonal effector T cells differentiated in the graft into TRM and subqeuntly caused allograft rejection. TRM identity was established by surface phenotype, transcriptional profile, and inability to recirculate in parabiosis and re-transplantation experiments. Graft TRM proliferated locally, produced IFNγ upon re-stimulation, and their in vivo depletion attenuated rejection. Importantly, the vast majority of antigen-specific and polyclonal TRM lacked phenotypic and transcriptional exhaustion markers. Single cell analysis of graft T cells early and late after transplantation identified a transcriptional program associated with transition to the tissue resident state that could serve as a platform for the discovery of therapeutic targets. Thus, recipient effector T cells differentiate into functional graft TRM that maintain rejection locally. Targeting these TRM could improve renal transplant outcomes.
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Project description:Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours.
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Project description:Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours
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Project description:CD8+ tissue resident memory T cells (TRM) develop from effectors that are recruited into peripheral tissues by infection or inflammation where they persist and provide defense against subsequent challenges. Long-term persistence of epidermal TRM requires autocrine TGFβ that is transactivated by integrins expressed on keratinocytes. In response to inflammation, the availability of TGFβ transactivation is limited. Antigen-experienced TRM that encountered antigen in the epidermis during their development are more fit and outcompete bystander TRM for TGFβ transactivation resulting in their enrichment in the epidermis. Transcriptomic analysis of endogenous epidermal TRM revealed that antigen-experienced TRM were enriched for TRM signature genes while bystander TRM retained the transcriptome of an earlier developmental state. Following antigen recall, antigen-experienced TRM displayed accelerated proliferation kinetics compared with bystanders that was determined by the TCR signal-strength during their differentiation the skin. Finally, antigen experienced TRM expressed TGFβRIII, which increases avidity of the TGFβRI/II receptor complex. Selective ablation of Tgfbr3 from antigen experienced TRM reduced their capacity to persist when TGFβ activation was limited thus rendering them phenotypically like bystander TRM. In sum, antigen-driven TCR signaling in the epidermis during TRM differentiation represents a required final step in ontogeny resulting in a lowered requirement on TGFβ transactivation for persistence and increased proliferation during recall responses that together result in the enhanced fitness of antigen-experience epidermal TRM.
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