scholarly journals c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Caroline Tizian ◽  
Annette Lahmann ◽  
Oliver Hölsken ◽  
Catalina Cosovanu ◽  
Michael Kofoed-Branzk ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nk Cell ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Negative Regulator ◽  
Signature Genes ◽  
Group 3 ◽  
Differentiation Status ◽  
Type 3

RORγt+ group 3 innate lymphoid cells (ILC3s) maintain intestinal homeostasis through secretion of type 3 cytokines such as interleukin (IL)−17 and IL-22. However, CCR6- ILC3s additionally co-express T-bet allowing for the acquisition of type 1 effector functions. While T-bet controls the type 1 programming of ILC3s, the molecular mechanisms governing T-bet are undefined. Here, we identify c-Maf as a crucial negative regulator of murine T-bet+ CCR6- ILC3s. Phenotypic and transcriptomic profiling of c-Maf-deficient CCR6- ILC3s revealed a hyper type 1 differentiation status, characterized by overexpression of ILC1/NK cell-related genes and downregulation of type 3 signature genes. On the molecular level, c-Maf directly restrained T-bet expression. Conversely, c-Maf expression was dependent on T-bet and regulated by IL-1β, IL-18 and Notch signals. Thus, we define c-Maf as a crucial cell-intrinsic brake in the type 1 effector acquisition which forms a negative feedback loop with T-bet to preserve the identity of CCR6- ILC3s.

scholarly journals c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Morgan E. Parker ◽  
Alejandro Barrera ◽  
Joshua D. Wheaton ◽  
Matthew K. Zuberbuehler ◽  
David S.J. Allan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Innate Lymphoid Cells ◽  
Chromatin Accessibility ◽  
Lymphoid Cells ◽  
Global Changes ◽  
Intestinal Immunity ◽  
Phenotypic Analysis ◽  
Group 3 ◽  
And Function

CCR6− group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and fully convert into ILC1s. The molecular mechanisms governing such plasticity are undefined. Here, we identified c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6− ILC3s, coupled with evaluation of global changes in transcriptome, chromatin accessibility, and transcription factor motif enrichment, revealed that c-Maf enforces ILC3 identity. c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf antagonized type 1 programming, largely through restraint of T-bet expression and function. Mapping of the dynamic changes in chromatin landscape accompanying CCR6− ILC3 development and ILC1 conversion solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.

scholarly journals Type 3 Innate Lymphoid Cells as Regulators of the Host-Pathogen Interaction

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Valle-Noguera ◽  
Anne Ochoa-Ramos ◽  
Maria José Gomez-Sánchez ◽  
Aranzazu Cruz-Adalia
Keyword(s):  
Transgenic Mice ◽  
Molecular Mechanisms ◽  
Specific Activity ◽  
Innate Lymphoid Cells ◽  
The Body ◽  
Lymphoid Cells ◽  
Intracellular Pathogens ◽  
Host Pathogen Interaction ◽  
Type 3

Type 3 Innate lymphoid cells (ILC3s) have been described as tissue-resident cells and characterized throughout the body, especially in mucosal sites and classical first barrier organs such as skin, gut and lungs, among others. A significant part of the research has focused on their role in combating pathogens, mainly extracellular pathogens, with the gut as the principal organ. However, some recent discoveries in the field have unveiled their activity in other organs, combating intracellular pathogens and as part of the response to viruses. In this review we have compiled the latest studies on the role of ILC3s and the molecular mechanisms involved in defending against different microbes at the mucosal surface, most of these studies have made use of conditional transgenic mice. The present review therefore attempts to provide an overview of the function of ILC3s in infections throughout the body, focusing on their specific activity in different organs.

scholarly journals Circadian rhythm–dependent and circadian rhythm–independent impacts of the molecular clock on type 3 innate lymphoid cells

2019 ◽  
Vol 4 (40) ◽  
pp. eaay7501 ◽  
Author(s):  
Qianli Wang ◽  
Michelle L. Robinette ◽  
Cyrielle Billon ◽  
Patrick L. Collins ◽  
Jennifer K. Bando ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Clock Genes ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Rhythmic Expression ◽  
Interleukin 22 ◽  
Circadian Clock Genes ◽  
Group 3 ◽  
Type 3 ◽  
The Impact

Many gut functions are attuned to circadian rhythm. Intestinal group 3 innate lymphoid cells (ILC3s) include NKp46+ and NKp46− subsets, which are RORγt dependent and provide mucosal defense through secretion of interleukin-22 (IL-22) and IL-17. Because ILC3s highly express some key circadian clock genes, we investigated whether ILC3s are also attuned to circadian rhythm. We noted circadian oscillations in the expression of clock and cytokine genes, such as REV-ERBα, IL-22, and IL-17, whereas acute disruption of the circadian rhythm affected cytokine secretion by ILC3s. Because of prominent and rhythmic expression of REV-ERBα in ILC3s, we also investigated the impact of constitutive deletion of REV-ERBα, which has been previously shown to inhibit the expression of a RORγt repressor, NFIL3, while also directly antagonizing DNA binding of RORγt. Development of the NKp46+ ILC3 subset was markedly impaired, with reduced cell numbers, RORγt expression, and IL-22 production in REV-ERBα–deficient mice. The NKp46− ILC3 subsets developed normally, potentially due to compensatory expression of other clock genes, but IL-17 secretion paradoxically increased, probably because RORγt was not antagonized by REV-ERBα. We conclude that ILC3s are attuned to circadian rhythm, but clock regulator REV-ERBα also has circadian-independent impacts on ILC3 development and functions due to its roles in the regulation of RORγt.

scholarly journals Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells

2017 ◽  
Vol 1 (27) ◽  
pp. 2679-2691 ◽  
Author(s):  
Ana Raykova ◽  
Paolo Carrega ◽  
Frank M. Lehmann ◽  
Robert Ivanek ◽  
Vanessa Landtwing ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nk Cells ◽  
Nk Cell ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Human Type ◽  
Key Points ◽  
Nk Cell Differentiation ◽  
Cytokine Stimulation ◽  
Type 3

Key Points Human type 3 ILCs acquire features of early differentiated NK cells upon cytokine stimulation. IL-12 and IL-15–differentiated human ILC3s acquire cytotoxicity and kill leukemic targets.

Pseudomonas aeruginosa Pneumonia Causes a Loss of Type-3 and an Increase in Type-1 Innate Lymphoid Cells in the Gut

2021 ◽  
Vol 265 ◽  
pp. 212-222
Author(s):  
Anja Fuchs ◽  
Sarbani Ghosh ◽  
Shin-Wen Chang ◽  
Grant V. Bochicchio ◽  
Isaiah R. Turnbull
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Type 3

Hobit confers tissue-dependent programs to type 1 innate lymphoid cells

2021 ◽  
Vol 118 (50) ◽  
pp. e2117965118
Author(s):  
Kentaro Yomogida ◽  
Tarin M. Bigley ◽  
Tihana Trsan ◽  
Susan Gilfillan ◽  
Marina Cella ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Salivary Glands ◽  
Intestinal Mucosa ◽  
Nk Cell ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Unique Cell ◽  
The Impact

Identification of type 1 innate lymphoid cells (ILC1s) has been problematic. The transcription factor Hobit encoded by Zfp683 has been proposed as a major driver of ILC1 programs. Using Zfp683 reporter mice, we showed that correlation of Hobit expression with ILC1s is tissue- and context-dependent. In liver and intestinal mucosa, Zfp683 expression correlated well with ILC1s; in salivary glands, Zfp683 was coexpressed with the natural killer (NK) master transcription factors Eomes and TCF1 in a unique cell population, which we call ILC1-like NK cells; during viral infection, Zfp683 was induced in conventional NK cells of spleen and liver. The impact of Zfp683 deletion on ILC1s and NK cells was also multifaceted, including a marked decrease in granzyme- and interferon-gamma (IFNγ)–producing ILC1s in the liver, slightly fewer ILC1s and more Eomes+ TCF1+ ILC1-like NK cells in salivary glands, and only reduced production of granzyme B by ILC1 in the intestinal mucosa. NK cell–mediated control of viral infection was unaffected. We conclude that Hobit has two major impacts on ILC1s: It sustains liver ILC1 numbers, while promoting ILC1 functional maturation in other tissues by controlling TCF1, Eomes, and granzyme expression.

scholarly journals Roles of Type 1, 2, and 3 Innate Lymphoid Cells in Herpes Simplex Virus 1 InfectionIn VitroandIn Vivo

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Satoshi Hirose ◽  
Shaohui Wang ◽  
Kati Tormanen ◽  
Yizhou Wang ◽  
Jie Tang ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Wild Type ◽  
Herpes Simplex Virus 1 ◽  
Type 3 ◽  
Deficient Mice ◽  
Hsv 1

ABSTRACTInnate lymphoid cells (ILCs) play important roles in host defense and inflammation. They are classified into three distinct groups based on their cytokine and chemokine secretion patterns and transcriptome profiles. Here, we show that ILCs isolated from mice can be infected with herpes simplex virus 1 (HSV-1) but that subsequent replication of the virus is compromised. After infection, type 2 ILCs expressed significantly higher levels of granulocyte colony-stimulating factor (G-CSF), interleukin 1α (IL-1α), IL-6, IL-9, RANTES, tumor necrosis factor alpha (TNF-α), CXCL1, CXCL2, CXCL10, CCL3, and CCL4 than infected type 1 or type 3 ILCs. Transcriptome-sequencing (RNA-seq) analysis of the ILCs 24 h after HSV-1 infection revealed that 77 herpesvirus genes were detected in the infected type 3 ILCs, whereas only 11 herpesvirus genes were detected in infected type 1 ILCs and 27 in infected type 2 ILCs. Compared with uninfected cells, significant upregulation of over 4,000 genes was seen in the HSV-1-infected type 3 ILCs, whereas 414 were upregulated in the infected type 1 ILCs and 128 in the infected type 2 ILCs. In contrast, in all three cell types, only a limited number of genes were significantly downregulated. Type 1, type 2, and type 3 ILC-deficient mice were used to gain insights into the effects of the ILCs on the outcome of ocular HSV-1 infection. No significant differences were found on comparison with similarly infected wild-type mice or on comparison of the three strains of deficient mice in terms of virus replication in the eyes, levels of corneal scarring, latency-reactivation in the trigeminal ganglia, or T-cell exhaustion. Although there were no significant differences in the survival rates of infected ILC-deficient mice and wild-type mice, there was significantly reduced survival of the infected type 1 or type 3 ILC-deficient mice compared with type 2 ILC-deficient mice. Adoptive transfer of wild-type T cells did not alter survival or any other parameters tested in the infected mice. Our results indicate that type 1, 2, and 3 ILCs respond differently to HSV-1 infectionin vitroand that the absence of type 1 or type 3, but not type 2, ILCs affects the survival of ocularly infected mice.IMPORTANCEIn this study, we investigated for the first time what roles, if any, innate lymphoid cells (ILCs) play in HSV-1 infection. Analysis of isolated ILCsin vitrorevealed that all three subtypes could be infected with HSV-1 but that they were resistant to replication. The expression profiles of HSV-1-induced cytokines/chemokines and cellular and viral genes differed among the infected type 1, 2, and 3 ILCsin vitro. While ILCs play no role or a redundant role in the outcomes of latency-reactivation in infected mice, absence of type 1 and type 3, but not type 2, ILCs affects the survival of infected mice.

scholarly journals Gata3 drives development of RORγt+ group 3 innate lymphoid cells

2014 ◽  
Vol 211 (2) ◽  
pp. 199-208 ◽  
Author(s):  
Nicolas Serafini ◽  
Roel G.J. Klein Wolterink ◽  
Naoko Satoh-Takayama ◽  
Wei Xu ◽  
Christian A.J. Vosshenrich ◽  
...  
Keyword(s):  
T Cell ◽  
Fetal Liver ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
T Cell Subsets ◽  
Mucosal Barrier ◽  
Hematopoietic Stem ◽  
Mucosal Surfaces ◽  
Gata3 Expression ◽  
Group 3

Group 3 innate lymphoid cells (ILC3) include IL-22–producing NKp46+ cells and IL-17A/IL-22–producing CD4+ lymphoid tissue inducerlike cells that express RORγt and are implicated in protective immunity at mucosal surfaces. Whereas the transcription factor Gata3 is essential for T cell and ILC2 development from hematopoietic stem cells (HSCs) and for IL-5 and IL-13 production by T cells and ILC2, the role for Gata3 in the generation or function of other ILC subsets is not known. We found that abundant GATA-3 protein is expressed in mucosa-associated ILC3 subsets with levels intermediate between mature B cells and ILC2. Chimeric mice generated with Gata3-deficient fetal liver hematopoietic precursors lack all intestinal RORγt+ ILC3 subsets, and these mice show defective production of IL-22 early after infection with the intestinal pathogen Citrobacter rodentium, leading to impaired survival. Further analyses demonstrated that ILC3 development requires cell-intrinsic Gata3 expression in fetal liver hematopoietic precursors. Our results demonstrate that Gata3 plays a generalized role in ILC lineage determination and is critical for the development of gut RORγt+ ILC3 subsets that maintain mucosal barrier homeostasis. These results further extend the paradigm of Gata3-dependent regulation of diversified innate ILC and adaptive T cell subsets.

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