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Transcriptional and Functional Programming of Decidual Innate Lymphoid Cells.

ABSTRACT: A successful pregnancy requires many physiological adaptations from the mother, including the establishment of tolerance toward the semiallogeneic fetus. Innate lymphoid cells (ILCs) have arisen as important players in immune regulation and tissue homeostasis at mucosal and barrier surfaces. Dimensionality reduction and transcriptomic analysis revealed the presence of two novel CD56Bright decidual ILCs that express low T-bet and divergent Eomes levels. Transcriptional correlation with recently identified first trimester decidual dNKs suggests that these novel decidual ILCs might be present throughout pregnancy. Functional testing with permutation analysis revealed production of multiple factors by individual cells, with a preference for IFN? and VEGF. Overall, our data suggests continuity of a unique decidual innate lymphocytes across pregnancy with a polyfunctional functional profile conducive for pregnancy.

SUBMITTER: Vazquez J

PROVIDER: S-EPMC6992589 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Transcriptional and Functional Programming of Decidual Innate Lymphoid Cells.

Vazquez Jessica J Chasman Deborah A DA Lopez Gladys E GE Tyler Chanel T CT Ong Irene M IM Stanic Aleksandar K AK

Frontiers in immunology 20200124

A successful pregnancy requires many physiological adaptations from the mother, including the establishment of tolerance toward the semiallogeneic fetus. Innate lymphoid cells (ILCs) have arisen as important players in immune regulation and tissue homeostasis at mucosal and barrier surfaces. Dimensionality reduction and transcriptomic analysis revealed the presence of two novel CD56<sup>Bright</sup> decidual ILCs that express low T-bet and divergent Eomes levels. Transcriptional correlation with ...[more]

PMID: 32038619

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Transcriptional and Functional Programming of Decidual Innate Lymphoid Cells

Project description:A successful pregnancy requires many physiological adaptations from the mother, including the establishment of tolerance towards the semiallogeneic fetus. Innate lymphoid cells (ILCs) have arisen as important players in immune regulation and tissue homeostasis at mucosal and barrier surfaces. Dimensionality reduction and transcriptomic analysis revealed the presence of two novel CD56Bright decidual ILCs, C10 and C2, that express divergent levels of Eomes. We found that decidual C10, C2, and cNKs correlated highly with previously identified first trimester decidual dNKs (dNK1-3). Functional analysis revealed polyfunctional profiles that depend on the nature of the stimulus, with a preference for IFNgamma and VEGF production. Overall, our data suggests persistence of pregnancy-specific decidual innate lymphocytes across pregnancy.

2020-01-24 | GSE129555 | GEO

Transcriptional and Functional Programming of Decidual Innate Lymphoid Cells

Project description:Transcriptional and Functional Programming of Decidual Innate Lymphoid Cells

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Deciphering the transcriptional switches of innate lymphoid cell programming: the right factors at the right time.

Project description:Innate lymphoid cells (ILCs) are increasingly recognised as an innate immune counterpart of adaptive T-helper (TH) cells. In addition to their similar effector cytokine production, there is a strong parallel between the transcription factors that control the differentiation of T(H)1, T(H)2 and T(H)17 cells and ILC groups 1, 2 and 3, respectively. Here, we review the transcriptional circuit that specifies the development of a common ILC progenitor and its subsequent programming into distinct ILC groups. Notch, GATA-3 (GATA-binding protein 3), Nfil3 (nuclear factor interleukin-3) and Id2 (inhibitor of DNA-binding 2) are identified as early factors that suppress B- and T-cell potentials and are turned on in favour of ILC commitment. Natural killer cells, which are the cytotoxic ILCs, develop along a pathway distinct from the rest of the helper-like ILCs that are derived from a common progenitor to all helper-like ILCs (CHILPs). PLZF(-) (promyelocytic leukaemia zinc-finger) CHILPs give rise to lymphoid tissue inducer cells, while PLZF(+) CHILPs have multilineage potential and could give rise to ILCs 1, 2 and 3. Such lineage specificity is dictated by the controlled expression of T-bet (T-box expressed in T cells), RORα (retinoic acid receptor-related orphan nuclear receptor-α), RORγt (retinoic acid receptor-related orphan nuclear receptor-γt) and AHR (aryl hydrocarbon receptor). In addition to the type of transcription factors, the developmental stages at which these factors are expressed are crucial in specifying the fate of the ILCs.

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Functional interactions between innate lymphoid cells and adaptive immunity.

Project description:Innate lymphoid cells (ILCs) are enriched at barrier surfaces of the mammalian body where they rapidly respond to host, microbial or environmental stimuli to promote immunity or tissue homeostasis. Furthermore, ILCs are dysregulated in multiple human diseases. Over the past decade, substantial advances have been made in identifying the heterogeneity and functional diversity of ILCs, which have revealed striking similarities to T cell subsets. However, emerging evidence indicates that ILCs also have a complex role in directly influencing the adaptive immune response in the context of development, homeostasis, infection or inflammation. In turn, adaptive immunity reciprocally regulates ILCs, which indicates that these interactions are a crucial determinant of immune responses within tissues. Here, we summarize our current understanding of functional interactions between ILCs and the adaptive immune system, discuss limitations and future areas of investigation, and consider the potential for these interactions to be therapeutically harnessed to benefit human health.

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

Project description: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.

| S-EPMC7025824 | biostudies-literature

Transcriptional and epigenetic networks of helper T and innate lymphoid cells.

Project description:The discovery of the specification of CD4(+) helper T cells to discrete effector 'lineages' represented a watershed event in conceptualizing mechanisms of host defense and immunoregulation. However, our appreciation for the actual complexity of helper T-cell subsets continues unabated. Just as the Sami language of Scandinavia has 1000 different words for reindeer, immunologists recognize the range of fates available for a CD4(+) T cell is numerous and may be underestimated. Added to the crowded scene for helper T-cell subsets is the continuously growing family of innate lymphoid cells (ILCs), endowed with common effector responses and the previously defined 'master regulators' for CD4(+) helper T-cell subsets are also shared by ILC subsets. Within the context of this extraordinary complexity are concomitant advances in the understanding of transcriptomes and epigenomes. So what do terms like 'lineage commitment' and helper T-cell 'specification' mean in the early 21st century? How do we put all of this together in a coherent conceptual framework? It would be arrogant to assume that we have a sophisticated enough understanding to seriously answer these questions. Instead, we review the current status of the flexibility of helper T-cell responses in relation to their genetic regulatory networks and epigenetic landscapes. Recent data have provided major surprises as to what master regulators can or cannot do, how they interact with other transcription factors and impact global genome-wide changes, and how all these factors come together to influence helper cell function.

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CD90 is not constitutively expressed in functional innate lymphoid cells.

Project description:Huge progress has been made in understanding the biology of innate lymphoid cells (ILC) by adopting several well-known concepts in T cell biology. As such, flow cytometry gating strategies and markers, such as CD90, have been applied to indentify ILC. Here, we report that most non-NK intestinal ILC have a high expression of CD90 as expected, but surprisingly a sub-population of cells exhibit low or even no expression of this marker. CD90-negative and CD90-low CD127+ ILC were present amongst all ILC subsets in the gut. The frequency of CD90-negative and CD90-low CD127+ ILC was dependent on stimulatory cues in vitro and enhanced by dysbiosis in vivo. CD90-negative and CD90-low CD127+ ILC were a potential source of IL-13, IFNγ and IL-17A at steady state and upon dysbiosis- and dextran sulphate sodium-elicited colitis. Hence, this study reveals that, contrary to expectations, CD90 is not constitutively expressed by functional ILC in the gut.

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Selective programming of CCR10(+) innate lymphoid cells in skin-draining lymph nodes for cutaneous homeostatic regulation.

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Functional Differences between Human NKp44(-) and NKp44(+) RORC(+) Innate Lymphoid Cells.

Project description:Human RORC(+) lymphoid tissue inducer cells are part of a rapidly expanding family of innate lymphoid cells (ILC) that participate in innate and adaptive immune responses as well as in lymphoid tissue (re) modeling. The assessment of a potential role for innate lymphocyte-derived cytokines in human homeostasis and disease is hampered by a poor characterization of RORC(+) innate cell subsets and a lack of knowledge on the distribution of these cells in adults. Here we show that functionally distinct subsets of human RORC(+) innate lymphoid cells are enriched for secretion of IL-17a or IL-22. Both subsets have an activated phenotype and can be distinguished based on the presence or absence of the natural cytotoxicity receptor NKp44. NKp44(+) IL-22 producing cells are present in tonsils while NKp44(-) IL-17a producing cells are present in fetal developing lymph nodes. Development of human intestinal NKp44(+) ILC is a programmed event that is independent of bacterial colonization and these cells colonize the fetal intestine during the first trimester. In the adult intestine, NKp44(+) ILC are the main ILC subset producing IL-22. NKp44(-) ILC remain present throughout adulthood in peripheral non-inflamed lymph nodes as resting, non-cytokine producing cells. However, upon stimulation lymph node ILC can swiftly initiate cytokine transcription suggesting that secondary human lymphoid organs may function as a reservoir for innate lymphoid cells capable of participating in inflammatory responses.

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