Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin

Luci, Carmelo; Reynders, Ana; Ivanov, Ivaylo I.; Cognet, Céline; Chiche, Laurent; Chasson, Lionel; Hardwigsen, Jean; Anguiano, Esperanza; Banchereau, Jacques; Chaussabel, Damien; Dalod, Marc; Littman, Dan R.; Vivier, Éric; Tomasello, Elena

doi:10.1038/ni.1681

Cited by 505 publications

(528 citation statements)

References 46 publications

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“…44 NK cells are usually rare in healthy skin. [45][46][47] This limits access to HPV-infected cells and reflects a minor role of NK cells in the natural HPV life cycle within the epidermis. However, during cancer growth infected cells come into reach for NK cell killing.…”

Section: Discussionmentioning

confidence: 99%

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

et al. 2016

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Human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (OSCC) are clinical and biological distinct from their HPV-unrelated counterparts. Patients with HPV-related OSCC display improved prognosis and therefore we investigated possible immune cell infiltrations associated with this tumor phenotype. We retrospectively analyzed a randomly selected cohort of 140 OSCC for presence of immune cells and HPV by immunohistochemistry and PCR followed by beadbased hybridization (Luminex technology). HPV prevalence was 24.3% as determined by positive staining of p16INK4a and detection of high risk HPV-DNA. We found significantly higher numbers of CD56 positive (CD561) cells in tumor and surrounding microenvironment in HPV-associated compared to HPV-negative OSCC (t-test: p 5 0.004 and p 5 0.002). For the entire cohort presence of CD561 cells was associated with increased overall survival independent from HPV (Kaplan-Meier: p 5 0.002; Cox regression: p 5 0.042). Presence of CD561 cells also correlated with a better outcome in HPV-negative and especially in HPV-negative OSCC with alcohol consumption 2 standard drinks per day (Kaplan-Meier: p 5 0.05 and p 5 0.003). Immunofluorescence localization of granular Granzyme B (GZMB) within CD561 cells and coexpression of CD16 and CD56 suggests that detected CD561 cells mainly represent cytotoxic Natural Killer (NK) cells. The fraction of potentially cytotoxic NK cells was significantly higher in HPV-associated compared to HPV-negative OSCC (Mann-Whitney-U-Test: p 5 0.011). The elevated abundance and activity of cytotoxic NK cells in OSCC with HPV driven carcinogenesis might contribute to favorable outcome in HPV-related OSCC.Head and neck cancer (HNC, comprising cancers of the oral cavity, lip, pharynx, nasopharynx and larynx) is ranking at position seven of newly diagnosed cancers and cause of cancer death worldwide, with 4.8% of total cancer incidence and 4.6% of total cancer mortality. 1 In particular oropharyngeal squamous cell carcinomas (OSCC) are related to high risk human papillomavirus (HPV) infection, which is accepted to be causally connected to HNC. 2,3 A recently published metaanalysis demonstrates a rising incidence of HPV1 OSCC in the United States from 21% (pre-1990), to 51% (1990-1999), to 65% (2000-2013). 4 Patients with HPV-associated OSCC show lower levels of disease recurrence and progression compared to patients with HPV-negative OSCC. Even with good loco regional tumor control, patients with HPV-associated OSCC have similar rates of distant metastases as patients with HPVnegative OSCC. Further efforts are needed to understand clinical and biological features of this distinct disease. 2,5,6 Molecular basis of HPV-associated cancers differ from their HPVunrelated counterparts. 3 Pathways related to cell cycle control or apoptosis (commonly affected by mutations in HPVnegative cancers) are silenced at protein level by HPVoncoproteins (mainly E6 and E7). It has been speculated that lower levels of genetic alterations contribute to better treat...

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Section: Discussionmentioning

confidence: 99%

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

et al. 2016

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“…Splenic iNK cells defined as CD3 2 CD19 2 NK1.1 + DX5 2 most likely contain the NKR-expressing LTi cells (NKR-LTi) (33)(34)(35)(36)(37). Because there is no surface marker to identify splenic NKR-LTi cells, except using the RORgt fate map mice (36, 37), we could not readily distinguish them from iNK cells in the spleen.…”

Section: Discussionmentioning

confidence: 99%

Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

Lee

Liou

Wang

et al. 2011

The Journal of Immunology

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NK cell development requires IL-15, which is “trans-presented” to IL-15Rβγ on NK cells by IL-15Rα on other cells. In this study, we report that different levels of IL-15 trans-presentation are required for different NK cell developmental events to reach full maturation status. Because the IL-15Rα intracellular domain has the capacity to recruit signaling molecules, we generated knockin and transgenic (Tg) mice that lack the intracellular domain to assess the role of the IL-15 trans-presentation level independent of the function of this domain. The level of IL-15Rα on various cells of these mice follows the order WT > Tg6 > knockin > Tg1 ≥ knockout. Bone marrow (BM)–derived dendritic cells prepared from these mice induced Stat5 phosphorylation in NK cells. The level of phospho-Stat5 correlated with the level of IL-15Rα on BMDCs, thus offering the opportunity to study quantitative effects of IL-15 trans-presentation on NK cell development in vivo. We found that NK cell homeostasis, mature NK cell differentiation, and acquisition of Ly49 receptor and effector functions require different levels of IL-15 trans-presentation input to achieve full status. All NK cell developmental events examined were quantitatively regulated by the IL-15Rα level of BM-derived and radiation-resistant accessory cells, but not by IL-15Rα of NK cells. We also found that IL-15Rα of radiation-resistant cells was more potent than IL-15Rα of BM-derived accessory cells in support of stage 2 to stage 3 splenic mNK differentiation. In summary, each examined developmental event required a particular level of IL-15 trans-presentation by accessory cells.

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“…Expression of ROR γ t is essential for the development and maturation of all members of the ILC3 family, including fetal LTi, adult LTi‐like ILC3 and NKp46 + ILC3 24, 25, 26, 27. ROR γ t‐expressing progenitors are present in the fetal liver of mice 14.…”

Section: Group 3 Innate Lymphoid Cell Developmentmentioning

confidence: 99%

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

2017

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SummaryGroup 3 innate lymphoid cells (ILC3), defined by expression of the transcription factor retinoid‐related orphan receptor γt, play key roles in the regulation of inflammation and immunity in the gastrointestinal tract and associated lymphoid tissues. ILC3 consist largely of two major subsets, NCR + ILC3 and LTi‐like ILC3, but also demonstrate significant plasticity and heterogeneity. Recent advances have begun to dissect the relationship between ILC3 subsets and to define distinct functional states within the intestinal tissue microenvironment. In this review we discuss the ever‐expanding roles of ILC3 in the context of intestinal homeostasis, infection and inflammation – with a focus on comparing and contrasting the relative contributions of ILC3 subsets.

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Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin

Cited by 505 publications

References 46 publications

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

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