Microbiota instruct IL-17A-producing innate lymphoid cells to promote skin inflammation in cutaneous leishmaniasis

p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Helvetica} span.s1 {color: #222222} span.s2 {font: 8.0px Helvetica} Innate lymphoid cells (ILCs) comprise a heterogeneous population of immune cells that maintain barrier function and can initiate a protective or pathological immune response upon infection. Here we show the involvement of IL-17A-producing ILCs in microbiota-driven immunopathology in cutaneous leishmaniasis. IL-17A-producing ILCs were RORgt + and were enriched in Leishmania major infected skin, and topical colonization with Staphylococcus epidermidis before L. major infection exacerbated the skin inflammatory responses and IL-17A-producing RORgt + ILC accumulation without impacting type 1 immune responses. IL-17A responses in ILCs were directed by Batf3 dependent CD103 + dendritic cells, and experiments using ILC deficient Rag1 -/- mice established that IL-17A + ILCs were sufficient in driving the inflammatory responses. As depletion of ILCs or neutralization of IL-17A diminished the microbiota mediated immunopathology. Taken together, this study indicates that the skin microbiota promotes RORgt + IL-17A-producing ILCs, which augment the skin inflammation in cutaneous leishmaniasis.

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Transcriptional regulatory networks that promote and restrict identities and functions of intestinal innate lymphoid cells

10.1101/465435 ◽

2018 ◽

Cited By ~ 1

Author(s):

Maria Pokrovskii ◽

Jason A. Hall ◽

David E. Ochayon ◽

Ren Yi ◽

Natalia S. Chaimowitz ◽

...

Keyword(s):

Regulatory Networks ◽

Inflammatory Diseases ◽

Innate Lymphoid Cells ◽

Chromatin Accessibility ◽

Immune Defense ◽

Lymphoid Cells ◽

Transcriptional Regulatory Networks ◽

Transcriptional Regulatory

SummaryInnate lymphoid cells (ILCs) can be subdivided into several distinct cytokine-secreting lineages that promote tissue homeostasis and immune defense but also contribute to inflammatory diseases. Accumulating evidence suggests that ILCs, similarly to other immune populations, are capable of phenotypic and functional plasticity in response to infectious or environmental stimuli. Yet the transcriptional circuits that control ILC identity and function are largely unknown. Here we integrate gene expression and chromatin accessibility data to infer transcriptional regulatory networks within intestinal type 1, 2, and 3 ILCs. We predict the “core” sets of transcription-factor (TF) regulators driving each ILC subset identity, among which only a few TFs were previously known. To assist in the interpretation of these networks, TFs were organized into cooperative clusters, or modules that control gene programs with distinct functions. The ILC network reveals extensive alternative-lineage-gene repression, whose regulation may explain reported plasticity between ILC subsets. We validate new roles for c-MAF and BCL6 as regulators affecting the type 1 and type 3 ILC lineages. Manipulation of TF pathways identified here might provide a novel means to selectively regulate ILC effector functions to alleviate inflammatory disease or enhance host tolerance to pathogenic microbes or noxious stimuli. Our results will enable further exploration of ILC biology, while our network approach will be broadly applicable to identifying key cell state regulators in otherin vivocell populations.

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Type 1 innate lymphoid cells: Soldiers at the front line of immunity

Biomedical Journal ◽

10.1016/j.bj.2020.10.001 ◽

2020 ◽

Author(s):

Tsukasa Nabekura ◽

Akira Shibuya

Keyword(s):

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Front Line

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Group 2 Innate Lymphoid Cells: Central Players in a Recurring Theme of Repair and Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21041350 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1350 ◽

Cited By ~ 3

Author(s):

Melina Messing ◽

Sia Cecilia Jan-Abu ◽

Kelly McNagny

Keyword(s):

T Regulatory Cells ◽

Inflammatory Responses ◽

Expression Profiles ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Helminth Infections ◽

Neonatal Immunity ◽

Group 2 ◽

Transcription Factor Expression

Innate lymphoid cells (ILCs) are recently discovered innate counterparts to the well-established T helper cell subsets and are most abundant at barrier surfaces, where they participate in tissue homeostasis and inflammatory responses against invading pathogens. Group 2 innate lymphoid cells (ILC2s) share cytokine and transcription factor expression profiles with type-2 helper T cells and are primarily associated with immune responses against allergens and helminth infections. Emerging data, however, suggests that ILC2s are also key regulators in other inflammatory settings; both in a beneficial context, such as the establishment of neonatal immunity, tissue repair, and homeostasis, and in the context of pathological tissue damage and disease, such as fibrosis development. This review focuses on the interactions of ILC2s with stromal cells, eosinophils, macrophages, and T regulatory cells that are common to the different settings in which type-2 immunity has been explored. We further discuss how an understanding of these interactions can reveal new avenues of therapeutic tissue regeneration, where the role of ILC2s is yet to be fully established.

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Type 1 innate lymphoid cells are associated with type 2 diabetes

Diabetes & Metabolism ◽

10.1016/j.diabet.2018.08.005 ◽

2019 ◽

Vol 45 (4) ◽

pp. 341-346 ◽

Cited By ~ 3

Author(s):

F. Liu ◽

H. Wang ◽

W. Feng ◽

X. Ye ◽

X. Sun ◽

...

Keyword(s):

Type 2 Diabetes ◽

Innate Lymphoid Cells ◽

Lymphoid Cells

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Natural Killer Cells and Type 1 Innate Lymphoid Cells Are New Actors in Non-alcoholic Fatty Liver Disease

Frontiers in Immunology ◽

10.3389/fimmu.2019.01192 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 13

Author(s):

Carmelo Luci ◽

Elodie Vieira ◽

Thibaut Perchet ◽

Philippe Gual ◽

Rachel Golub

Keyword(s):

Liver Disease ◽

Natural Killer Cells ◽

Fatty Liver ◽

Natural Killer ◽

Fatty Liver Disease ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells

Nature Immunology ◽

10.1038/ni.3800 ◽

2017 ◽

Vol 18 (9) ◽

pp. 1004-1015 ◽

Cited By ~ 218

Author(s):

Yulong Gao ◽

Fernando Souza-Fonseca-Guimaraes ◽

Tobias Bald ◽

Susanna S Ng ◽

Arabella Young ◽

...

Keyword(s):

Nk Cells ◽

Innate Lymphoid Cells ◽

Lymphoid Cells

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VIP-producing enteric neurons interact with innate lymphoid cells to regulate feeding-dependent intestinal epithelial barrier functions

10.1101/721464 ◽

2019 ◽

Cited By ~ 2

Author(s):

Jhimmy Talbot ◽

Paul Hahn ◽

Lina Kroehling ◽

Henry Nguyen ◽

Dayi Li ◽

...

Keyword(s):

Food Consumption ◽

Metabolic Diseases ◽

Inflammatory Responses ◽

Innate Lymphoid Cells ◽

Lipid Binding ◽

Lymphoid Cells ◽

Lipid Absorption ◽

Enteric Neurons ◽

Barrier Functions ◽

Enhanced Expression

ABSTRACTThe intestinal mucosa serves as both a conduit for uptake of food-derived nutrients and microbiome-derived metabolites and as a barrier that prevents tissue invasion by microbes and tempers inflammatory responses to the myriad contents of the lumen. How the intestine coordinates physiological and immune responses to food consumption to optimize nutrient uptake while maintaining barrier functions remains unclear. Here, we describe how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses controlled by type 3 innate lymphoid cells (ILC3)1-3. Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP)4. Projections of VIP-producing neurons (VIPergic neurons) in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2 or VPAC2). ILC3 production of IL-22, which is up-regulated by commensal microbes such as segmented filamentous bacteria (SFB)5-7, is inhibited upon engagement of VIPR2. As a consequence, there is a reduction in epithelial cell-derived antimicrobial peptide, but enhanced expression of lipid-binding proteins and transporters8. During food consumption, activation of VIPergic neurons thus enhances growth of epithelial-associated SFB and increases lipid absorption. Our results reveal a feeding- and circadian-regulated dynamic intestinal neuro-immune circuit that promotes a trade-off between IL-22-mediated innate immune protection and efficiency of nutrient absorption. Modulation of this pathway may hence be effective for enhancing resistance to enteropathogen2,3,9 and for treatment of metabolic diseases.

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