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Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program.

ABSTRACT: Mesenteric lymph node (mLN) T cells undergo tissue adaptation upon migrating to intestinal lamina propria and epithelium, ensuring appropriate balance between tolerance and resistance. By combining mouse genetics with single-cell and chromatin analyses, we uncovered the molecular imprinting of gut epithelium on T cells. Transcriptionally, conventional and regulatory (T_reg) CD4⁺ T cells from mLN, lamina propria and intestinal epithelium segregate based on the gut layer they occupy; trajectory analysis suggests a stepwise loss of CD4 programming and acquisition of an intraepithelial profile. T_reg cell fate mapping coupled with RNA sequencing and assay for transposase-accessible chromatin followed by sequencing revealed that the T_reg cell program shuts down before an intraepithelial program becomes fully accessible at the epithelium. Ablation of CD4-lineage-defining transcription factor ThPOK results in premature acquisition of an intraepithelial lymphocyte profile by mLN T_reg cells, partially recapitulating epithelium imprinting. Thus, coordinated replacement of the circulating lymphocyte program with site-specific transcriptional and chromatin changes is necessary for tissue imprinting.

SUBMITTER: London M

PROVIDER: S-EPMC8251700 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

Project description:Mesenteric lymph node (mLN) T cells undergo tissue adaptation upon migrating to intestinal lamina propria (LP) and intraepithelial (IE) compartments, ensuring appropriate balance between tolerance and resistance. By combining mouse genetics with single-cell and chromatin analyses, we addressed the molecular imprinting of gut epithelium on T cells. Transcriptionally, conventional and regulatory (Treg) CD4+ T cells from mLN, LP and IE segregate based on the gut layer they occupy; trajectory analysis suggests a stepwise loss of CD4-programming and acquisition of an intraepithelial profile. Treg fate–mapping coupled with RNA– and ATAC–sequencing revealed that the Treg program shuts down before an intraepithelial program becomes fully accessible at the epithelium. Ablation of CD4 lineage–defining transcription factor ThPOK results in premature acquisition of an IEL profile by mLN Tregs, partially recapitulating epithelium imprinting. Thus, coordinated replacement of circulating lymphocyte program with site–specific transcriptional and chromatin changes is necessary for tissue imprinting.

2021-01-04 | GSE146292 | GEO

Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

Project description:Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

| PRJNA610060 | ENA

Transcriptional profiles reveal a stepwise developmental program of memory CD8(+) T cell differentiation.

Project description:The generation of CD8(+) T-cell memory is a major aim of vaccination. While distinct subsets of CD8(+) T-cells are generated following immunization that differ in their ability to confer long-term immunity against infection, the transcriptional profiles of these subsets within endogenous vaccine-induced CD8(+) T cell responses have not been resolved. Here, we measure global transcriptional profiles of endogenous effector (TEFF), effector memory (TEM) and central memory (TCM) CD8(+) T-cells arising from immunization with three distinct prime-boost vaccine regimens. While a proportion of transcripts were uniquely regulated within distinct CD8(+) T cell populations, we observed progressive up- or down-regulation in the expression of a majority of differentially expressed transcripts when subsets were compared in the order TN>TCM>TEM>TEFF. Strikingly, when we compared global differences in gene expression between TN, TCM, TEM and TEFF cells with known transcriptional changes that result when CD8(+) T cells repetitively encounter antigen, our analysis overwhelmingly favored a model whereby cumulative antigen stimulation drives differentiation specifically from TN>TCM>TEM>TEFF and this was common to all vaccines tested. These findings provide insight into the molecular basis of immunological memory and identify potential biomarkers for characterization of vaccine-induced responses and prediction of vaccine efficacy.

| S-EPMC6439469 | biostudies-literature

Stepwise arteriovenous fate acquisition during mammalian vasculogenesis.

Project description:Arteriovenous (AV) differentiation is a critical step during blood vessel formation and stabilization. Defects in arterial or venous fate lead to inappropriate fusion of vessels, resulting in damaging arteriovenous shunts. While many studies have unraveled the molecular underpinnings that drive AV fate, surprisingly, the spatiotemporal emergence of arteries and veins in mammalian embryos remains unknown. Here, we examine artery and vein specification and differentiation during vasculogenesis. We show that the first intraembryonic vessels formed are arteries, which differentiate in a stepwise manner. By contrast, veins emerge later, progressively forming after embryonic turning. In addition, we demonstrate that hemodynamic flow is not required for arterial specification, but is required for maintenance of select arterial markers. Together, our results provide a first spatiotemporal analysis of mammalian AV cell fate establishment and anatomy, as well as a delineation of a molecular toolkit for analysis of arteries and veins during early vessel development.

| S-EPMC3192916 | biostudies-literature

Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance.

Project description:Unrelenting environmental challenges to the gut epithelium place particular demands on the local immune system. In this context, intestinal intraepithelial lymphocytes (IEL) compose a large, highly conserved T cell compartment, hypothesized to provide a first line of defence via cytolysis of dysregulated intestinal epithelial cells (IEC) and cytokine-mediated re-growth of healthy IEC. Here we show that one of the most conspicuous impacts of activated IEL on IEC is the functional upregulation of antiviral interferon (IFN)-responsive genes, mediated by the collective actions of IFNs with other cytokines. Indeed, IEL activation in vivo rapidly provoked type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium. Consistent with this, activated IEL mediators protected cells against virus infection in vitro, and pre-activation of IEL in vivo profoundly limited norovirus infection. Hence, intraepithelial T cell activation offers an overt means to promote the innate antiviral potential of the intestinal epithelium.

| S-EPMC4479038 | biostudies-literature

Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation.

Project description:The intestinal epithelium harbors large populations of activated and memory lymphocytes, yet these cells do not cause tissue damage in the steady state. We investigated how intestinal T cell effector differentiation is regulated upon migration to the intestinal epithelium. Using gene loss- and gain-of-function strategies, as well as reporter approaches, we showed that cooperation between the transcription factors T-bet and Runx3 resulted in suppression of conventional CD4(+) T helper functions and induction of an intraepithelial lymphocyte (IEL) program that included expression of IEL markers such as CD8?? homodimers. Interferon-? sensing and T-bet expression by CD4(+) T cells were both required for this program, which was distinct from conventional T helper differentiation but shared by other IEL populations, including TCR??(+)CD8??(+) IELs. We conclude that the gut environment provides cues for IEL maturation through the interplay between T-bet and Runx3, allowing tissue-specific adaptation of mature T lymphocytes.

| S-EPMC4287410 | biostudies-literature

Osteopontin and iCD8? Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis.

Project description:Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes, ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses, such as survival of Th17 cells and homeostasis of NK cells among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. In this study, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCR??+, TCR?+CD4+, TCR?+CD4+CD8?+, and TCR?+CD8??+ cells in comparison with wild-type mice. For some IEL subpopulations, the decrease in cell numbers could be attributed to apoptosis and reduced cell division. Moreover, we show in vitro that exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8? IEL but not TCR??+ IEL, TCR?+ IEL, or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8? cells in the homeostasis of IEL.

| S-EPMC7175606 | biostudies-literature

Stepwise acquisition of pyrimethamine resistance in the malaria parasite.

Project description:The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa.

| S-EPMC2715478 | biostudies-literature

The Neutrophil-Lymphocyte Ratio Predicts Recurrence of Cervical Intraepithelial Neoplasia.

Project description:OBJECTIVE: The purpose of the present study was to determine the prognostic significance of the neutrophil-lymphocyte ratio (NLR) in recurrence of cervical intraepithelial neoplasia (CIN). METHODS: We evaluated the NLR as a prognostic marker in the entire cohort of 230 patients who had undergone surgical resection and were diagnosed with CIN. Subjects were categorized into two different groups based on the NLR (NLR-high and NLR-low) using cutoff values determined by receiver operating characteristic (ROC) analysis. The primary research objective for this study was to validate the impact of the NLR on recurrence-free survival (RFS) in patients with CIN. The secondary objective was to evaluate the impact of other hematologic parameters on RFS in CIN patients. RESULTS: Using the entire cohort, the most appropriate NLR cut-off value for CIN recurrence selected on the ROC curve was 2.1. The NLR-low and NLR-high groups included 167 (72.6%) and 63 patients (27.4%), respectively. According to Kaplan-Meier analysis, RFS rates during the entire follow-up period were considerably lower in the NLR-high group than in the NLR-low group (P = 0.0125). In multivariate survival analysis using Cox proportional hazard model, we identified the NLR, absolute eosinophil count (AEC), hemoglobin concentration, and mean corpuscular volume (MCV) as valuable prognostic factors that impact RFS. CONCLUSIONS: The NLR is an independent prognosticator for RFS following surgical resection in CIN patients. We also found that the AEC, hemoglobin level, and MCV were strongly associated with RFS, as determined by multivariate analysis using a Cox model. These hematological parameters might provide additional prognostic value beyond that offered by standard clinicopathologic parameters.

| S-EPMC5560137 | biostudies-other

Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria.

Project description:Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disease of hematopoietic stem cells that is associated with hemolysis, marrow failure, and thrombophilia. PNH has been considered a monogenic disease that results from somatic mutations in the gene encoding PIGA, which is required for biosynthesis of glycosylphosphatidylinisotol-anchored (GPI-anchored) proteins. The loss of certain GPI-anchored proteins is hypothesized to provide the mutant clone with an extrinsic growth advantage, but some features of PNH argue that there are intrinsic drivers of clonal expansion. Here, we performed whole-exome sequencing of paired PNH+ and PNH- fractions on samples taken from 12 patients as well as targeted deep sequencing of an additional 36 PNH patients. We identified additional somatic mutations that resulted in a complex hierarchical clonal architecture, similar to that observed in myeloid neoplasms. In addition to mutations in PIGA, mutations were found in genes known to be involved in myeloid neoplasm pathogenesis, including TET2, SUZ12, U2AF1, and JAK2. Clonal analysis indicated that these additional mutations arose either as a subclone within the PIGA-mutant population, or prior to PIGA mutation. Together, our data indicate that in addition to PIGA mutations, accessory genetic events are frequent in PNH, suggesting a stepwise clonal evolution derived from a singular stem cell clone.

| S-EPMC4191017 | biostudies-literature

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