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Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity.

ABSTRACT: Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)⁺ ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR⁺ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.

SUBMITTER: Fiancette R

PROVIDER: S-EPMC7611981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Reciprocal Transcription Factor Networks Govern Tissue-Resident ILC3 Subset Function and Identity

Project description:Innate lymphoid cells (ILCs) play important roles in health and tissue homeostasis. While the transcriptional networks that drive their development have been defined, the transcriptional requirements that support the phenotypes and functions of mature tissue-resident populations remain poorly understood. Here we employed combinatorial inducible deletion of core transcription factors (TFs) to test how co-operative and antagonistic networks operate to control function and identity. Utilizing single cell sequencing and epigenetic profiling we dissect the complex interplay between ROR family member TFs and T-bet in determining the function and phenotype of ILC3 and NCR-lineage ILCs, defining the ontogeny and surface phenotype across a continuum of ILC3s and mature ILC1s in the small intestine, alongside the differential requirements for ROR family TFs in the maintenance of effector functions and phenotype in mature ILCs. Combined, our data demonstrates how TF networks integrate in vivo to sustain effector functions and restrict alternative differentiation programmes.

2021-09-23 | GSE163149 | GEO

Reciprocal Transcription Factor Networks Govern Tissue-Resident ILC3 Subset Function and Identity

Project description:Reciprocal Transcription Factor Networks Govern Tissue-Resident ILC3 Subset Function and Identity

| PRJNA685109 | ENA

Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3.

Project description:Innate lymphoid cells (ILCs) are tissue-resident effector cells with roles in tissue homeostasis, protective immunity, and inflammatory disease. Group 3 ILCs (ILC3s) are classically defined by the master transcription factor RORγt. However, ILC3 can be further subdivided into subsets that share type 3 effector modules that exhibit significant ontological, transcriptional, phenotypic, and functional heterogeneity. Notably lymphoid tissue inducer (LTi)-like ILC3s mediate effector functions not typically associated with other RORγt-expressing lymphocytes, suggesting that additional transcription factors contribute to dictate ILC3 subset phenotypes. Here, we identify Bcl6 as a subset-defining transcription factor of LTi-like ILC3s in mice and humans. Deletion of Bcl6 results in dysregulation of the LTi-like ILC3 transcriptional program and markedly enhances expression of interleukin-17A (IL-17A) and IL-17F in LTi-like ILC3s in a manner in part dependent upon the commensal microbiota-and associated with worsened inflammation in a model of colitis. Together, these findings redefine our understanding of ILC3 subset biology.

| S-EPMC7615641 | biostudies-literature

Bcl6 is a subset defining transcription factor of Lymphoid Tissue inducer-like ILC3

Project description:Innate lymphoid cells (ILC) are tissue-resident effector cells with important roles in tissue homeostasis, protective immunity and inflammatory disease. Current nomenclature divides ILC into subsets based on the expression of master transcription factors and effector cytokine programs. In mucosal barrier tissues, group 3 ILC (ILC3) have been defined by the expression of the master transcription factor RORgt. However, ILC3 can be further subdivided into two major subsets – natural cytotoxicity receptor-expressing (NCR+) ILC3 and lymphoid tissue inducer (LTi)-like ILC3 which share type 3 effector modules but also exhibit significant ontological, transcriptional, phenotypic and functional heterogeneity. In particular, LTi-like ILC3 exhibit effector functions not typically associated with other RORgt-expressing lymphocytes, provoking the hypothesis that other master transcription factors may contribute to LTi-like ILC3 biology. Here we identify Bcl6 as an LTi-like ILC3 associated transcription factor in both mice and humans. Deletion of Bcl6 led to dysregulation of the LTi-like ILC3 transcriptional program and changes to subset-specific phenotypic markers and effector functions. Strikingly, loss of Bcl6 enhanced expression of the type 3 effector cytokines IL-17A and IL-17F in LTi-like ILC3, which was found to be in part dependent upon the commensal microbiota. Together these findings implicate Bcl6 as an ILC3 subset-defining transcription factor and part of a network that confers phenotype and function on LTi-like ILC3. Our study further provides a missing link to redefine analogous immune modules in innate and adaptive lymphocyte responses.

2023-10-31 | GSE228852 | GEO

Bcl-2 supports survival and metabolic fitness of quiescent tissue-resident ILC3.

Project description:Group 3 innate lymphoid cells (ILC3) are potent effector cells with critical roles in enforcing immunity, barrier integrity and tissue homeostasis along the gastrointestinal tract. ILC3 are considered primarily tissue-resident cells, seeding the gastrointestinal tract during embryonic stages and early life. However, the mechanisms through which mature ILC3 are maintained within adult tissues are poorly understood. Here, we report that lymphoid tissue-inducer-like (LTi-like) ILC3 exhibit minimal turnover in the healthy adult intestinal tract, persist for extended periods of time, and display a quiescent phenotype. Strikingly, during enteric bacterial infection LTi-like ILC3 also exhibit negligible hematopoietic replenishment and remain non-proliferative, despite robustly producing cytokines. Survival of LTi-like ILC3 was found to be dependent upon the balance between the metabolic activity required to drive effector function and anti-apoptotic programs. Notably, the pro-survival protein B-cell lymphoma-2 (Bcl-2) was required for the survival of LTi-like ILC3 ex vivo but was rendered partially dispensable if mitochondrial respiration was inhibited. Together we demonstrate LTi-like ILC3 are a tissue-resident, quiescent population that persist independently of hematopoietic replenishment to survive within the intestinal microenvironment.

| S-EPMC10564625 | biostudies-literature

Bcl6 is a subset defining transcription factor of Lymphoid Tissue inducer-like ILC3

Project description:Bcl6 is a subset defining transcription factor of Lymphoid Tissue inducer-like ILC3

| PRJNA951730 | ENA

Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function.

Project description:Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription, and packaging. Here, we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues in the steady state and in tumors. Tfam-deficient Tregs have reduced proliferation and Foxp3 expression upon glucose deprivation in vitro. Tfam deficiency preferentially affects gene activation in Tregs through regulation of DNA methylation, with enhanced methylation in the TSDR of the Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and stability, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role of Tfam-mediated mitochondrial respiration in Tregs to regulate inflammation and anti-tumor immunity.

| S-EPMC6679941 | biostudies-literature

The Transcription Factor ThPOK Regulates ILC3 Lineage Homeostasis and Function During Intestinal Infection.

Project description:Innate lymphoid cells (ILCs) have been identified as a heterogeneous population of lymphocytes that mirrors the cytokine and transcriptional profile of adaptive T cells. The dynamic balance between key transcription factors determines the heterogeneity, plasticity, and functions of ILC subsets. The transcription factor ThPOK is highly conserved in biological evolution and exerts pivotal functions in the differentiation of T cells. However, the function of ThPOK in ILC3s has not been identified. Here, we found that ThPOK regulated the homeostasis of ILC3s, as mice lacking ThPOK showed decreased NKp46+ ILC3s and increased CCR6- NKp46- ILC3s. ThPOK-deficient mice were more sensitive to S. typhimurium infection due to the impaired IFN-γ secretion of NKp46+ ILC3s. Furthermore, ThPOK participates in ILC3-mediated control of C. rodentium infection by negatively regulating IL-17A secretion. ThPOK preserves the identity of NKp46+ ILC3s by repressing RORγt, which indirectly releases T-bet expression. On the molecular level, ThPOK directly binds to Rorc and Il23r to restrain their expression which further modulates IL-17A secretion. Collectively, our analysis revealed a critical role of ThPOK in the homeostasis and functions of ILC3 subsets.

| S-EPMC9285022 | biostudies-literature

Transcription factor Tlx1 marks a subset of lymphoid tissue organizer-like mesenchymal progenitor cells in the neonatal spleen.

Project description:The spleen is comprised of spatially distinct compartments whose functions, such as immune responses and removal of aged red blood cells, are tightly controlled by the non-hematopoietic stromal cells that provide regionally-restricted signals to properly activate hematopoietic cells residing in each area. However, information regarding the ontogeny and relationships of the different stromal cell types remains limited. Here we have used in vivo lineage tracing analysis and in vitro mesenchymal stromal cell assays and found that Tlx1, a transcription factor essential for embryonic spleen organogenesis, marks neonatal stromal cells that are selectively localized in the spleen and retain mesenchymal progenitor potential to differentiate into mature follicular dendritic cells, fibroblastic reticular cells and marginal reticular cells. Furthermore, by establishing a novel three-dimensional cell culture system that enables maintenance of Tlx1-expressing cells in vitro, we discovered that signals from the lymphotoxin ? receptor and TNF receptor promote differentiation of these cells to express MAdCAM-1, CCL19 and CXCL13, representative functional molecules expressed by different subsets of mature stromal cells in the spleen. Taken together, these findings indicate that mesenchymal progenitor cells expressing Tlx1 are a subset of lymphoid tissue organizer-like cells selectively found in the neonatal spleen.

| S-EPMC6938487 | biostudies-literature

T cells regulate lymph node-resident ILC populations in a tissue and subset-specific way.

Project description:Innate lymphoid cells (ILCs) have been shown to be significantly affected in the small intestine lamina propria and secondary lymphoid organs (SLOs) of conventional lymphopenic mice. How ILCs are regulated by adaptive immunity in SLOs remains unclear. In T cell-deficient mice, ILC2s are significantly increased in the mesenteric lymph nodes (MLNs) at the expense of CCR6+ ILC3s, which are nonetheless increased in the peripheral lymph nodes (PLNs). Here, we show that T cells regulate lymph node-resident ILCs in a tissue- and subset-specific way. First, reducing microbial colonization from birth restored CCR6+ ILC3s in the MLNs of T cell-deficient mice. In contrast, T cell reconstitution resulted in the contraction of both MLNs ILC2s and PLNs ILC3s, whereas antagonizing microbial colonization from birth had no impact on these populations. Finally, the accumulation of MLNs ILC2s was partly regulated by T cells through stroma-derived IL-33.

| S-EPMC7907429 | biostudies-literature

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