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Memory-like Natural Killer cells become resident in non-lymphoid tissue to maintain tissue health

ABSTRACT: Tissue health is dictated by the capacity to respond to perturbations and then return to homeostasis. Mechanisms that initiate, maintain, and regulate immune responses in tissues are therefore essential. Adaptive immunity plays a key role in these responses, with memory and tissue-residency being cardinal features. A corresponding role for innate cells is unknown. Here we have identified a population of innate lymphocytes that we term tissue-resident memory-like natural killer (NKRM) cells. In response to murine cytomegalovirus infection, we show that circulating NK cells were recruited in a CX3CR1-dependent manner to the salivary glands where they formed NKRM cells, a long-lived tissue-resident population that prevented autoimmunity via TRAIL-dependent elimination of CD4+ T cells. Thus, NK cells develop adaptive-like features, including long-term residency in nonlymphoid tissues, to modulate inflammation, restore immune equilibrium and preserve tissue health. Modulating the functions of NKRM cells may provide additional strategies to treat inflammatory and autoimmune diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE222613 | GEO | 2023/02/13

REPOSITORIES: GEO

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Infection induces tissue resident memory NK cells that safeguard tissue

Project description:Tissue health is dictated by the capacity to respond to perturbations and then return to a homeostatic state. Thus, mechanisms that initiate, maintain and regulate immune responses in tissues are essential. The adaptive immune system has been ascribed a principal role in these responses, with memory and tissue-residency being cardinal features of immune protection in tissues. Whether there is a corresponding role for innate cells is unknown. Here we identify a population of innate lymphocytes that we term tissue-resident memory-like natural killer (NKRM) cells. In response to murine cytomegalovirus infection, we show that circulating NK cells are recruited to the salivary glands where they form NKRM cells, a long-lived tissue-resident population that prevents autoimmunity and safeguards organ function. Thus, NK cells develop adaptive-like features, including long-term residency in nonlymphoid tissues, to modulate inflammation, restore immune equilibrium and preserve tissue health. Modulating the functions of NKRM cells may provide new strategies to treat inflammatory and autoimmune diseases.

2023-02-13 | GSE219243 | GEO

Genome wide mapping of chromatin accessibility in resident memory precursor cells [ATAC-seq]

Project description:The transcription factor (TF) networks that regulate the differentiation of resident versus circulating memory CD8+ T cells are incompletely understood. Here we show that the TF Bcl11b restricts gut resident memory (Trm) cell differentiation, while promoting splenic T central memory (Tcm) and effector memory (Tem) cell differentiation. The reduction of Bcl11b-deficient splenic Tcm and Tem cells was not due to major alterations in their programs, but rather due to the increased homing of their precursors to the small intestine. However, Bcl11b-deficient resident memory precursor cells upregulated residency program, including the TFs Ahr and Prdm1 (encoding Blimp1), and downregulated Tcf7, which restricts the residency program and promotes tissue egress. Bcl11b directly bound at Ahr and Prdm1, as well as at Tcf7 genes. Abrogating Ahr and Prdm1, or restoration of Tcf7 expression in Bcl11b-deficient cells led to partial correction of the excessive resident memory cell differentiation. Functionally, Bcl11b-deficient memory CD8+ T cells had an impaired recall response, but anti-tumor immunity was increased in adoptive cell therapy. Bcl11b also repressed the residency program in human CD8+ T cells and human Bcl11b low tumor-infiltrating lymphocytes showed increased residency gene expression. Thus, Bcl11b plays a critical role in balancing the circulating and tissue residency programs and reveals a potential novel target for cancer immunotherapies.

2023-06-08 | GSE186281 | GEO

Impact of Bcl11b on the transcriptome of CD8+ T cell subsets[RNA-seq]

2023-06-08 | GSE186283 | GEO

Mapping Bcl11b binding in in vitro differentiated resident memory T cells [ChIP-seq]

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A non-lymphoid origin for lymph node resident memory T cells

Project description:Immunosurveillance of secondary lymphoid organs (SLO) is performed by central memory T cells that recirculate through blood. Resident memory T cells (TRM) remain parked in nonlymphoid tissues and often stably express CD69. We recently identified TRM within SLO, and this study addresses knowledge gaps in their origin and phenotype. Parabiosis of ‘dirty’ mice revealed that CD69 expression is insufficient to infer stable residence. Using selective depletion strategies, parabiosis, imaging, tissue grafting, and photoactivatable T cells, we report that restimulation of TRM within the skin or mucosa results in a substantial increase in TRM that patrol all regions of draining lymph nodes. SLO TRM were derived from nonlymphoid tissue residents. Transcriptional profiling and flow cytometry revealed a refined phenotype shared between both nonlymphoid and SLO TRM. These data demonstrate the nonlymphoid origin of SLO TRM and suggest vaccination strategies by which memory CD8 T cell immunosurveillance can be regionalized to specific lymph nodes.

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2022-05-24 | GSE182511 | GEO

Transcriptional profiling of human hepatic NK cell subpopulations

Project description:To identify potential functional roles of liver-resident NK cells we performed RNA sequencing on FACS sorted NK cell subpopulations from liver perfusates (n=5) and healthy blood controls (n=5). Full-length transcripts were sequenced from low-input samples using a modified version of the SMART-Seq2 protocol. Hepatic CD56brightCD16- and CD56brightCD16+ samples upregulate genes associated with tissue residency.

2022-04-09 | GSE200319 | GEO

The inositol phosphtase INPP4B sustains ILC1s and intratumoral NK cells through an AKT-driven survival pathway

Project description:Innate lymphoid cells (ILCs) are a heterogeneous population of lymphocytes that coordinate early immune responses and maintain tissue homeostasis. Type 1 immune responses are mediated by natural killer (NK) cells and group 1 ILCs (ILC1s). Despite their shared features, NK cells and ILC1s display profound differences among various tissue microenvironments. Here, we identify the inositol polyphosphatase INPP4B as a hallmark feature of tissue-resident ILC1s and intratumoral NK cells using a scRNA-seq atlas of tissue-associated and circulating NK/ILC1s. Conditional deletion of Inpp4b in ILC1s and NK cells reveals that it is necessary for the homeostasis of tissue-resident ILC1s but not circulating NK cells at steady-state. Inpp4b-deficient cells display increased rates of apoptosis and reduced activation of the pro-survival molecule AKT. Furthermore, expression of Inpp4b by NK/ILC1s is necessary for their presence in the intratumoral environment and lack of Inpp4b impairs antitumor immunity. These findings highlight INPP4B as a novel regulator of tissue residency and antitumor function in ILC1s and NK cells.

2024-01-01 | GSE250334 | GEO

Multimodal profiling reveals site-specific adaptation and tissue residency hallmarks of γδ T cells across organs in mice

Project description:γδ T cells perform heterogeneous functions in homeostasis and disease across tissues. However, it is unclear whether these roles correspond to distinct γδ subsets or to a homogeneous population of cells exerting context-dependent functions. Here, by cross-organ multimodal single-cell profiling, we reveal that various mouse tissues harbor unique site-adapted γδ subsets. Epidermal and intestinal intraepithelial γδ T cells are transcriptionally homogeneous and exhibit epigenetic hallmarks of functional diversity. Through parabiosis experiments, we uncovered cellular states associated with cytotoxicity, innate-like rapid IFN-γ production and tissue repair functions displaying tissue residency hallmarks. Notably, our observations nuance the link between IL-17-producing γδ T cells and tissue residency. Moreover, transcriptional programs associated with tissue-resident γδ T cells are analogous to those of CD8+ tissue-resident memory T cells. Altogether, this study provides the first multimodal landscape of tissue-adapted γδ T cells, revealing heterogeneity, lineage relationships and their tissue residency program.

2023-11-05 | GSE222454 | GEO

Resident T Cell Repertoires

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