Dissecting human <scp>ILC</scp> heterogeneity: more than just three subsets

Simoni, Yannick; Newell, Evan W.

doi:10.1111/imm.12862

Cited by 55 publications

(48 citation statements)

References 87 publications

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“…While human and murine ILCs shared expression of some surface markers, there were enough distinctions and inconsistencies between them to raise fundamental questions about the biology of human ILCs (Klose and Artis, 2016;Mjö sberg and Spits, 2016;Montaldo et al, 2016;Simoni and Newell, 2018). Murine ILC populations comprise three distinct subsets, whose functional capacities are tailored to the environments in which they reside (Ebbo et al, 2017, Kim et al, 2016, Klose and Artis, 2016.…”

Section: Discussionmentioning

confidence: 99%

Spatial and Temporal Mapping of Human Innate Lymphoid Cells Reveals Elements of Tissue Specificity

Yudanin¹,

Schmitz²,

Flamar³

et al. 2019

Immunity

140

163

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Highlights d In contrast to mice, human ILCs are less strictly compartmentalized d ILC subset composition is differentially impacted by tissue localization d Tissue environment drives transcriptional heterogeneity in a subset-dependent way d ILC1 exhibit greater transcriptional heterogeneity in mucosal versus lymphoid sites SUMMARY Innate lymphoid cells (ILC) play critical roles in regulating immunity, inflammation, and tissue homeostasis in mice. However, limited access to non-diseased human tissues has hindered efforts to profile anatomically-distinct ILCs in humans. Through flow cytometric and transcriptional analyses of lymphoid, mucosal, and metabolic tissues from previously healthy human organ donors, here we have provided a map of human ILC heterogeneity across multiple anatomical sites. In contrast to mice, human ILCs are less strictly compartmentalized and tissue localization selectively impacts ILC distribution in a subset-dependent manner. Tissue-specific distinctions are particularly apparent for ILC1 populations, whose distribution was markedly altered in obesity or aging. Furthermore, the degree of ILC1 population heterogeneity differed substantially in lymphoid versus mucosal sites. Together, these analyses comprise a comprehensive characterization of the spatial and temporal dynamics regulating the anatomical distribution, subset heterogeneity, and functional potential of ILCs in non-diseased human tissues.

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Section: Discussionmentioning

confidence: 99%

Spatial and Temporal Mapping of Human Innate Lymphoid Cells Reveals Elements of Tissue Specificity

Yudanin¹,

Schmitz²,

Flamar³

et al. 2019

Immunity

140

163

View full text Add to dashboard Cite

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“…Whether analogous populations of mouse ILC1 and cNK exist in humans is an important question. Phenotypically distinct NK cells are present in human peripheral blood and tissues, but whether these represent ILC1 and cNK remains controversial due to overlapping phenotypes and conflicting reports (44,45). HCMV-infected humans often show expansions of CD57 ϩ NKG2C high NK cells in blood, and these cells play an important role in controlling viremia in transplant of PFU from the infected spleen, liver, or total SG were quantified at different days following the infection by doing a standard plaque assay in NIH 3T3 cells as described previously (50).…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus Evades TRAIL-Mediated Innate Lymphoid Cell 1 Defenses

Picarda

Ghosh

McDonald

et al. 2019

J Virol

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Cytomegalovirus (CMV) establishes a lifelong infection facilitated, in part, by circumventing immune defenses mediated by tumor necrosis factor (TNF)-family cytokines. An example of this is the mouse CMV (MCMV) m166 protein, which restricts expression of the TNF-related apoptosis-inducing ligand (TRAIL) death receptors, promoting early-phase replication. We show here that replication of an MCMV mutant lacking m166 is also severely attenuated during viral persistence in the salivary glands (SG). Depleting group I innate lymphoid cells (ILCs) or infecting Trail−/− mice completely restored persistent replication of this mutant. Group I ILCs are comprised of two subsets, conventional natural killer cells (cNK) and tissue-resident cells often referred to as innate lymphoid type I cells (ILC1). Using recently identified phenotypic markers to discriminate between these two cell types, their relative expression of TRAIL and gamma interferon (IFN-γ) was assessed during both early and persistent infection. ILC1 were found to be the major TRAIL expressers during both of these infection phases, with cNK expressing very little, indicating that it is ILC1 that curtail replication via TRAIL in the absence of m166-imposed countermeasures. Notably, despite high TRAIL expression by SG-resident ILC1, IFN-γ production by both ILC1 and cNK was minimal at this site of viral persistence. Together these results highlight TRAIL as a key ILC1-utilized effector molecule that can operate in defense against persistent infection at times when other innate control mechanisms may be muted and highlight the importance for the evolution of virus-employed countermeasures. IMPORTANCE Cytomegalovirus (a betaherpesvirus) is a master at manipulating immune responses to promote its lifelong persistence, a result of millions of years of coevolution with its host. Using a one-of-a-kind MCMV mutant unable to restrict expression of the TNF-related apoptosis-inducing ligand death receptors (TRAIL-DR), we show that TRAIL-DR signaling significantly restricts both early and persistent viral replication. Our results also reveal that these defenses are employed by TRAIL-expressing innate lymphoid type I cells (ILC1) but not conventional NK cells. Overall, our results are significant because they show the key importance of viral counterstrategies specifically neutralizing TRAIL effector functions mediated by a specific, tissue-resident subset of group I ILCs.

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“…For example, ILC2 are characterized by secretion of IL-5 and IL-13 after stimulation with IL-25 or IL-33 [18], while ILC3 are characterized by the expression of IL-22 and IL-17 [18]. Between the populations of ILC2 and ILC3, there is the possibility of mutual transition: under the influence of IL-12, ILC2 CD3 - [28] CD4 - [68] CD27 + [69] CD56 - [69] CD94 - [69] CD127 + [69] NKp46 - [68] CD3 - [28] CD4 -[68] CD127 + [68] NKp46 - [68] CRTH2 + [66] IL-18R + [66] CD161 + [66] IL-25R + [66] IL-33R + [66] IL-17R + [28] CD3 - [28] CD4 - [68] CD56 - [69] CD127 + [68] NKp44 + [66] IL-18R + [66] IL-1R + [66] IL-23R + [66] Secreted cytokines IFNγ [68] TNFα [66] IFNγ [68] TNFα [66] IL-5, IL-13 [68] IFNγ [66] IL-4 [66] IL-3, IL-8 [28] IL-9, IL-21 [28] IL-17, IL-22 [66,68] IL-2, TNFα [66] Transcription factors T-bet [69] Eomes [69] T-bet [69] RORα [68] GATA3 [68] RORγt [68] and ILC3 can be transdifferentiated into ILC1. Under the influence of IL-4 and IL-23, ILC1 in turn can differentiate into ILC2, and IL-23 will promote differentiation...…”

Section: Lymphoid Cells Of Innate Immunitymentioning

confidence: 99%

Differentiation of Nk Cells. A Look Through the Prism of Transcription Factors and Intracellular Messengers

et al. 2019

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Резюме. Все лимфоидные клетки относят к врожденному или адаптивному звену иммунитета согласно механизмам реализации иммунных реакций. Реализация функциональной активности NKклеток не связана с процессами предварительной активации в результате контакта с антигеном, реаранжировкой генов антигенраспознающих рецепторов и клональной пролиферацией. В связи с этим NK-клетки традиционно относят к клеткам врожденного иммунитета. Ранее полагали, что единственной популяцией лимфоидных клеток врожденного иммунитета являются NK-клетки, однако в последние годы в литературе появляется все больше свидетельств существования различных популяций этих клеток, что послужило основанием для выделения общего кластера под названием «лимфоидные клетки врожденного иммунитета» (Innate Lymphoid Cells -ILC). По классификации ILC NK-клетки относят к первой группе врожденных лимфоидных клеток согласно их общим функциональным характеристикам, а также участию транскрипционного фактора T-bet в их дифференцировке. Сложность, многоэтапность и частично нелинейный характер дифференцировки NK-клеток связаны с влиянием клеточного микроокружения, последовательной экспрессией транскрипционных факторов и активацией различных внутриклеточных путей передачи сигнала в NK-клетках. В обзоре рассматривается место NK-клеток в классификации ILC, основные транскрипционные факторы, участвующие в процессе дифференцировки NK-клеток. Авторами предпринимается попытка обобщить основные пути внутриклеточной передачи сигнала в NK-клетках в зависимости от активации цитокинами, присутствующими в клеточном микроокружении и оказывающими влияние на NK-клетки. Особым объектом дифференцировки NK-клеток являются NK-клетки децидуальной оболочки при беременности. Кроме NK-клеток, в составе децидуальной оболочки присутствуют стромальные клетки, клетки трофобласта, макрофаги. В обзоре рассмотрен частный случай влияния клеток микроокружения на экспрессию транскрипционных факторов и активацию внутриклеточных мессенджеров NK-клеток на примере клеток трофобласта. Открытое в настоящее время многообра-Mikhailova V.A. et al. Михайлова В.А. и др. Medical Immunology (Russia)/Meditsinskaya Immunologiya Медицинская Иммунология зие NK-клеток, реализующееся в зависимости от микроокружения в процессе их дифференцировки, требует дальнейшего изучения. Работа поддержана грантом НШ-2873.2018.7. Участие Баженова Д.О. поддержано стипендией Президента РФ СП-2836.2018.4.Ключевые слова: NK-клетки, лимфоидные клетки врожденного иммунитета, дифференцировка, транскрипционные факторы, внутриклеточные мессенджеры, децидуальные NK-клетки, трофобласт Abstract. All lymphoid cells are referred to as an innate or adaptive immunity unit in terms of the mechanisms of performing immune reactions. The functional activity of natural killer (NK) cells is not associated with pre-activation processes resulting from contact with antigen, rearrangement of antigen-recognition receptor genes, and clonal proliferation. In this regard, NK cells are traditionally referred to as cells of innate immunity. Previously, it was belie...

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Dissecting human ILC heterogeneity: more than just three subsets

Cited by 55 publications

References 87 publications

Spatial and Temporal Mapping of Human Innate Lymphoid Cells Reveals Elements of Tissue Specificity

Spatial and Temporal Mapping of Human Innate Lymphoid Cells Reveals Elements of Tissue Specificity

Cytomegalovirus Evades TRAIL-Mediated Innate Lymphoid Cell 1 Defenses

Differentiation of Nk Cells. A Look Through the Prism of Transcription Factors and Intracellular Messengers

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