Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues

Ali, Ayad; Canaday, Laura M.; Feldman, H. Alex; Cevik, Hilal; Moran, Michael T; Rajaram, Sanjeeth; Lakes, Nora; Tuazon, Jasmine; Seelamneni, Harsha; Krishnamurthy, Durga; Blass, Eryn; Barouch, Dan H.; Waggoner, Stephen N.

doi:10.1172/jci146686

Cited by 27 publications

(8 citation statements)

References 32 publications

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“…Most proliferating stage 4 and 5 NK cells are not in proximity to IL-7, IL-15, or Flt3L expressing cells, suggesting that other factors, including IL-2, can promote mature NK cell proliferation in situ (12). In addition, the increased frequency of interactions between mature NK cells and CD4+ T cells underscores the role of NK cells in assisting in the coordination of adaptive immunity (59)(60)(61). Finally, while these data identify certain correlations between chemokine receptors and ligands, it should be noted that trafficking in tissue is complex and directed by chemokine signaling, cell adhesion, and physical properties of tissue.…”

Section: Discussionmentioning

confidence: 99%

Mapping human natural killer cell development in pediatric tonsil by imaging mass cytometry and high-resolution microscopy

Hegewisch-Solloa,

Melsen,

Ravichandran

et al. 2023

Preprint

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Natural killer (NK) cells develop from CD34+progenitors in a stage-specific manner defined by changes in cell surface receptor expression and function. Secondary lymphoid tissues, including tonsil, are sites of human NK cell development. Here we present new insights into human NK cell development in pediatric tonsil using cyclic immunofluorescence and imaging mass cytometry. We show that NK cell subset localization and interactions are dependent on NK cell developmental stage and tissue residency. NK cell progenitors are found in the interfollicular domain in proximity to cytokine-expressing stromal cells that promote proliferation and maturation. Mature NK cells are primarily found in the T-cell rich parafollicular domain engaging in cell-cell interactions that differ depending on their stage and tissue residency. The presence of local inflammation results in changes in NK cell interactions, abundance, and localization. This study provides the first comprehensive atlas of human NK cell development in secondary lymphoid tissue.

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Section: Discussionmentioning

confidence: 99%

Mapping human natural killer cell development in pediatric tonsil by imaging mass cytometry and high-resolution microscopy

Hegewisch-Solloa,

Melsen,

Ravichandran

et al. 2023

Preprint

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“…4M-N). Both BTLA and CXCR3 were shown to induce immunosuppressive NK phenotypes 52, 53 . In contrast, TNFRSF4 (CD134), GZMB, and TBX21 (TBET) were higher in the CD56 + CD57 + cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Human endogenous retrovirus activation contributes to biliary atresia pathogenesis through re-education of resident macrophages

Sheng

Zhang

Zhao

et al. 2022

Preprint

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Biliary atresia (BA) is a life-threatening neonatal fibro-inflammatory disease characterized by hepatic fibrosis, cirrhosis, and end-stage liver failure. BA is also the most frequent indication of pediatric liver transplantation globally. Despite the devastating condition of BA, the pathogenesis mechanism is unknown. Viral infection has been suggested to be associated with BA, but definitive evidence to support this hypothesis is not available. To elucidate the virus-associated pathogenesis mechanism of BA and to understand the immune ecosystem, we performed single-cell transcriptomic and proteomic profiling of BA livers. We detected human endogenous virus (HERV) in infants with BA and their parents. HERV was mainly found in FOLR2+ resident macrophages, T cells, and NK cells. In addition, HERV activation re-educated the fetal-derived FOLR2+ resident macrophages, and reactive oxygen species scavenging neutrophil recruitment was impaired in patients with BA and HERV+, due to FOLR2+ resident macrophage re-education. Furthermore, we showed depletion of FOLR2+ resident macrophage and N-acetylcysteine treatment could rescue the liver damage in BA. Overall, our study revealed the HERV-associated immunopathology mechanism of BA. These results contribute to potential diagnosis and immunotherapy strategies for BA.

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“…Among these, CXCR3-A and CXCR3-B are the two most studied isomers ( 10 ). CXCR3-A is mainly expressed in activated T lymphocytes and natural killer (NK) cells ( 11 , 12 ). At the same time, CXCR3-B is primarily distributed on vascular endothelial cells, while relatively little research has been conducted on CXCR3-alt, which is currently believed to exert biological effects mainly in combination with interferon-induced T cell alpha chemoattractant (I-TAC).…”

Section: Composition and Role Of Cxcr3 And Its Ligandsmentioning

confidence: 99%

The role of CXCR3 and its ligands in cancer

Wang¹,

Zhang²,

Wang³

et al. 2022

Front. Oncol.

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Chemokines are a class of small cytokines or signaling proteins that are secreted by cells. Owing to their ability to induce directional chemotaxis of nearby responding cells, they are called chemotactic cytokines. Chemokines and chemokine receptors have now been shown to influence many cellular functions, including survival, adhesion, invasion, and proliferation, and regulate chemokine levels. Most malignant tumors express one or more chemokine receptors. The CXC subgroup of chemokine receptors, CXCR3, is mainly expressed on the surface of activated T cells, B cells, and natural killer cells, and plays an essential role in infection, autoimmune diseases, and tumor immunity by binding to specific receptors on target cell membranes to induce targeted migration and immune responses. It is vital to treat infections, autoimmune diseases, and tumors. CXCR3 and its ligands, CXCL9, CXCL10, and CXCL11, are closely associated with the development and progression of many tumors. With the elucidation of its mechanism of action, CXCR3 is expected to become a new indicator for evaluating the prognosis of patients with tumors and a new target for clinical tumor immunotherapy. This article reviews the significance and mechanism of action of the chemokine receptor CXCR3 and its specific ligands in tumor development.

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Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues

Cited by 27 publications

References 32 publications

Mapping human natural killer cell development in pediatric tonsil by imaging mass cytometry and high-resolution microscopy

Mapping human natural killer cell development in pediatric tonsil by imaging mass cytometry and high-resolution microscopy

Human endogenous retrovirus activation contributes to biliary atresia pathogenesis through re-education of resident macrophages

The role of CXCR3 and its ligands in cancer

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