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Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy subjects

ABSTRACT: Tissue-resident memory T cells (TRM) persist locally in non-lymphoid tissues where they provide front-line defense against recurring insults. TRM at barrier surfaces express the markers CD103 and/or CD69 which function to retain them in epithelial tissues. In humans, neither the long-term migratory behavior of TRM nor their ability to re-enter the circulation and potentially migrate to distant tissue sites have been investigated. Using tissue explant cultures, we found that CD4+CD69+CD103+ TRM in human skin can downregulate CD69 and exit the tissue. Additionally, we identified a skin-tropic CD4+CD69-CD103+ population in human lymph and blood that is transcriptionally, functionally and clonally related to the CD4+CD69+CD103+ TRM population in the skin. Using a skin xenograft model, we confirmed that a fraction of the human cutaneous CD4+CD103+ TRM population can re-enter circulation, and migrate to secondary human skin sites where they re-assume a TRM phenotype. Thus, our data challenge current concepts regarding the strict tissue compartmentalization of CD4+ T cell memory in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131770 | GEO | 2019/05/25

REPOSITORIES: GEO

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Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets II

Project description:Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However transcriptional heterogeneity of human intestinal TRM cells remains undefined. Here, we investigated transcriptional and functional heterogeneity of human TRM cells through study of donor-derived intestinal TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identified two distinct transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We defined a transcriptional signature discriminating these two CD8+ populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft and lymphocytes from healthy gut confirmed the two CD8+ TRM phenotypes. CD103+ CD8+ TRM cells produced IL-2, and demonstrated greater polyfunctional cytokine production, while β2-integrin+ CD69+ CD103- TRM cells had higher granzyme expression. Phenotypic and functional analysis of intestinal CD4+ T cells identified many parallels, including a distinct β2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4+ and CD8+ TRM cells.

2020-12-05 | GSE162686 | GEO

Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets I

2020-12-05 | GSE162685 | GEO

RNA-seq transcriptome analysis of epidermal CD8+CD103+CD49a+ and CD8+CD103+CD49- T cells from healthy human skin

Project description:We report the transcriptome analysis of epidermal CD8 tissue resident memory T (TRM) cells from healthy human skin. Specifically, epidermal CD8+CD103+CD49a+ and CD8+CD103+CD49- TRM cells from healthy human skin were sorted by FACS. Differential gene expression analysis revealed functional dichotomy of epidermal CD8+CD103+CD49a+ and CD8+CD103+CD49- TRM cells.

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Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter (Circulation)

Project description:The human brain is populated by perivascular CD8+ and CD4+ T cells with a tissue-resident memory T (TRM)-cell phenotype. In multiple sclerosis (MS), these cells associate with white matter (WM) and, to a lesser extent, grey matter (GM) lesions. We here investigated the transcriptional and functional profile of brain-resident T cells. Of n=11 subsequent post-mortem brain donors, we isolated CD8+ and CD4+ effector memory and effector memory re-expressing CD45RA T cells from blood and CD8+ and CD4+ CD69+ T cells from corpus callosum WM and cortical GM. Additionally, brain CD69+ T cells were sorted from subcortical WM, corpus callosum WM, and medulla WM/GM of n=3–5 brain donors as well as from paired normal-appearing WM and GM and from WM and GM lesions of n=6 MS brain donors. In all donors, WM and GM T cells were overwhelmingly CD69+CD103+/-. Bulk RNA sequencing of CD8+ and CD4+ CD69+ T cells revealed TRM-cell signatures, as marked by differential expression of, among others, SELL (CD62L), ITGA1 (CD49a), and S1PR1. Notably, gene expression hardly differed between lesional and normal-appearing WM CD8+ and CD4+ CD69+ T cells in MS brains. Genes up-regulated in brain TRM cells were MS4A1 (CD20) and SPP1 (osteopontin, OPN). OPN is also abundantly expressed by microglia and has been shown to inhibit T-cell activity. In line with the increased presence of OPN in active MS lesions, we noticed a reduced production of the inflammatory cytokines IL-2, TNF, and IFNγ by MS lesion-derived CD8+ and CD4+ T cells ex vivo. This study discloses essential characteristics of human brain CD8+ and CD4+ TRM cells in non-MS and MS post-mortem WM and GM, reports OPN as a generic product of brain-resident immune cells, and shows a tight control of the activation state of TRM cells in MS lesions.

2022-12-05 | GSE216026 | GEO

Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (MS)

2022-12-05 | GSE216028 | GEO

Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (Location)

2022-12-05 | GSE216027 | GEO

Longitudinal transcriptional profiling of CD8 cells in response to infection and vaccination across tissues

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2022-08-17 | GSE198980 | GEO

An unconventional integrin b3 and CD103 heterodimer improves the anti-tumor immunity of tissue-resident T cells

Project description:Current cancer immunotherapies promote recovery of CD103+ tissue-resident memory T cells (Trm) population of the tumor-infiltrating T lymphocytes (TILs). However, not all treated patients exhibit improved anti-tumor immunity and survival, likely due to the immunophenotypical diversity among the CD103+ Trm TILs. Utilising multifaceted proteomics approaches and patients’ clinical analyses, we discovered an unusual subset of CD8+ Trm TILs expressing non-canonical integrin β3 early during T cells activation. The integrin β3 surprisingly heterodimerises with CD103 on T cells, leading to unconventional granulysin-mediated cytotoxicity, elevated alternative bioenergy usage and efficient T cell migration, with minimal overall exhaustion. Importantly, early-stage non-small cell lung carcinoma (NSCLC) patients with enriched presence of integrin β3+CD103+ Trm TILs exhibited better clinical prognosis, with improved T cell immunophenotype, hence confirming the beneficial role of this unusual subset of Trm TILs. These unconventional anti-tumor T cell features provide new avenues and future opportunities for designing better translational immunotherapy strategies.

2024-02-14 | PXD031794 | Pride

Trigger-happy resident memory CD4+ T cells inhabit the human lungs.

Project description:Resident memory T-cells (TRM) reside in the lung epithelium and mediate protective immunity against respiratory pathogens. While lung CD8+ TRM have been extensively characterized, the properties of CD4+ TRM remain unclear. Here we determined the transcriptional signature of CD4+ TRM, identified by the expression of CD103, retrieved from human lung resection material. Various tissue homing molecules were specifically upregulated on CD4+ TRM, while expression of tissue egress and lymph node homing molecules were low. CD103+ TRM expressed low levels of T-bet, only a small portion expressed Eomes, and while the mRNA levels for Hobit were increased, protein expression was absent. On the other hand, the CD103+ TRM showed a Notch signature. CD4+CD103+ TRM constitutively expressed high transcript levels of numerous cytotoxic mediators, which was functionally reflected by a fast recall response, magnitude of cytokine production, and a high degree of polyfunctionality. Interestingly, the superior cytokine production appears to be due to an accessible IFNγ locus and was partially due to rapid translation of preformed mRNA. Our studies provide a molecular understanding of the maintenance and potential function of CD4+ TRM in the human lung. Understanding the specific properties of CD4+ TRM is required to rationally improve vaccine design.

2017-11-08 | GSE103527 | GEO

Tissue adaptation and clonal segregation of human memory T cells in barrier sites

Project description:T lymphocytes migrate to barrier sites after exposure to pathogen-derived antigens to provide localized immune defense and long-term surveillance. However, unique tissue adaptations of barrier T cells and the extent to which they participate in clonal networks remains unclear. In this study, we utilized our organ donor tissue resource to examine T cells in barrier sites (skin, lung, jejunum), their associated lymph nodes, other lymphoid tissues (spleen and bone marrow), and circulation. By integrating multiple single-cell protein and transcript profiling technologies, we demonstrate that human barrier sites contain site-adapted memory T cell populations, including tissue-resident memory T cells (TRM) that exhibit both shared barrier TRM signatures and tissue-specific residency profiles. Additionally, incorporating T cell receptor and RNA-sequencing analysis, we show that lung T cell clones form global networks with clones in lymphoid sites and circulation, and comprise widely disseminated clones of TEM/TEMRA subset that display distinct effector phenotypes; while T cells in skin and jejunum are predominantly TRM and participate primarily in localized clonal networks with tissue-associated lymph nodes but are largely compartmentalized.

2022-11-14 | GSE206507 | GEO

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