The Tec kinase ITK is essential for ILC2 survival and epithelial integrity in the intestine

Cho, Hyoung-Soo; Reboldi, Andrea; Hall, Jason A.; Berg, Leslie J.

doi:10.1038/s41467-019-08699-9

Cited by 22 publications

(19 citation statements)

References 61 publications

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“…In an autoimmune disease setting, the migratory function of CD4 + T cells to multiple organs, such as liver and lung, is severely impaired in the absence of ITK ( 9 ). We previously examined the status of Itk −/− T cells in the lung, as this is an important route of MHV68 infection ( 38 ). Unlike the cellular defect in the gut, Itk −/− mice do not show any significant reduction in T cell numbers in the lung at steady-state.…”

Section: Discussionmentioning

confidence: 99%

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CD8+ T Cells Require ITK-Mediated TCR Signaling for Migration to the Intestine

Cho

Shin

et al. 2020

ImmunoHorizons

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The Tec kinase IL-2-inducible T cell kinase (ITK) regulates the expression of TCR-induced genes. Itk 2/2 T cell responses are impaired but not absent. ITK inhibition prevented colitis disease progression and impaired T cell migration to the colon in mice. To examine the function of ITK in T cell migration to the intestine, we examined the number of gut T cells in Itk 2/2 mice and then evaluated their expression of gut-homing receptors. Combined with in vitro murine T cell stimulation and in vivo migration assay using congenic B6 mice, we demonstrated an essential role for ITK in T cell migration to the intestine in mice. Reconstitution of Itk 2/2 mouse CD8 + T cells with IFN regulatory factor 4 restored gut-homing properties, providing mechanistic insight into the function of ITK-mediated signaling in CD8 + T cell migration to the intestinal mucosa in mice. ImmunoHorizons, 2020, 4: 57-71.

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Section: Discussionmentioning

confidence: 99%

“…Intestinal lymphocytes were processed as previously described (12,38). In brief, intestinal tissues were opened longitudinally and cut into 2-3-cm pieces.…”

Section: Isolation Of Intraepithelial Lymphocyte and Lamina Propria Lmentioning

confidence: 99%

CD8+ T Cells Require ITK-Mediated TCR Signaling for Migration to the Intestine

Cho

Shin

et al. 2020

ImmunoHorizons

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“…[peritoneal cavity (10), lymph node, omentum (11), bone marrow (12), and gut (13)(14)(15)], with various types of infection observed in B cell subsets (12,(16)(17)(18), myeloid cells (macrophages and dendritic cells) (10,16), endothelial cells (19), and intestinal epithelial cells (13). The vast array of potential viral reservoirs calls for an efficient and robust method to track infection.…”

Section: Introductionmentioning

confidence: 99%

Optimized detection of acute MHV68 infection with a reporter system identifies large peritoneal macrophages as a dominant target of primary infection

Riggs

Medina

Perrenoud

et al. 2020

Preprint

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Investigating the dynamics of virus-host interactions in vivo remains an important challenge, often limited by the ability to directly identify virally-infected cells. Here, we combine detection of a beta-lactamase activated fluorescent substrate with full spectrum flow cytometry to identify primary targets of murine gammaherpesvirus 68 (MHV68) infection in the peritoneal cavity. By optimizing substrate and detection conditions, we were able to achieve multiparameter characterization of infected cells and the ensuing host response. MHV68 infection leads to a pronounced increase in immune cells, with CD8+ T cells increasing by 3 days, and total infiltrate peaking around 8 days post-infection. MHV68 infection results in near elimination of large peritoneal macrophages by 8 days post-infection, and a concordant increase in small peritoneal macrophages and monocytes. Infection is associated with prolonged changes to myeloid cells, with a distinct population of MHC IIhigh large peritoneal macrophages emerging by 14 days. Targets of MHV68 infection could be readily detected. Between 1 to 3 days post-infection, MHV68 infects ~5-10% of peritoneal cells, with >75% being large peritoneal macrophages. By 8 days post-infection, the frequency of MHV68 infection is reduced at least 10-fold, with infection primarily in small peritoneal macrophages, with few infected dendritic cells and B cells. MHV68 infection at 3 days post-infection contains both lytic and latent infection, consistent with the identification of cells with active reporter gene expression. Our findings demonstrate the utility of the beta-lactamase MHV68 reporter system for high throughput single-cell analysis and identify dynamic changes during primary gammaherpesvirus infection.ImportanceIdentifying virally-infected cells in vivo is key to tracking viral infection and understanding host-pathogen interactions. The ability to further characterize and phenotype virally-infected cells is technically challenging. We use a mouse gammaherpesvirus, MHV68, expressing a reporter gene to identify infected cells during primary infection via flow cytometry. Optimization using this reporter system allowed us to further characterize infected cells via multiparameter full spectrum flow cytometry. Our study provides a technical model for high throughput single-cell immunophenotyping methods in the context of gammaherpesvirus infection. Furthermore, we show that acute MHV68 infection in the peritoneal cavity dramatically changes the immune landscape of this tissue, results in a high number of infected macrophages at early times, and is characterized by both lytic and latent infection within immune cells.

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“…Several immune cell populations infiltrate the CRC TME by modulating the tumor response (56). Among them, ILC2s, that are abundant in the intestinal mucosa (57), have been reported in CRC patients, to be recruited to the tumor site suggesting their potential role in CRC development and progression (58). However, there is still no robust data in human or mouse models, clarifying the role of ILC2s in colorectal tumorigenesis.…”

Section: Ilc2s In Cancers Of the Gastrointestinal Systemmentioning

confidence: 99%

ILC2s: New Actors in Tumor Immunity

et al. 2019

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Innate lymphoid cells (ILCs) represent the most recently identified family of innate lymphocytes that act as first responders, maintaining tissue homeostasis and protecting epithelial barriers. In the last few years, group 2 ILCs (ILC2s) have emerged as key regulators in several immunological processes such as asthma and allergy. Whilst ILC2s are currently being evaluated as novel targets for immunotherapy in these diseases, their involvement in tumor immunity has only recently begun to be deciphered. Here, we provide a comprehensive overview of the pleiotropic roles of ILC2s in different tumor settings. Furthermore, we discuss how different therapeutic approaches targeting ILC2s could improve the efficacy of current tumor immunotherapies.

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The Tec kinase ITK is essential for ILC2 survival and epithelial integrity in the intestine

Cited by 22 publications

References 61 publications

CD8+ T Cells Require ITK-Mediated TCR Signaling for Migration to the Intestine

CD8+ T Cells Require ITK-Mediated TCR Signaling for Migration to the Intestine

Optimized detection of acute MHV68 infection with a reporter system identifies large peritoneal macrophages as a dominant target of primary infection

ILC2s: New Actors in Tumor Immunity

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