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Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection

ABSTRACT: Mucosal barrier surfaces serve as the critical first line of defense separating our bodies from the plethora of pathogenic microorganisms that inhabit our environment. Adaptive immunity provides life-long protection through the generation of a central and effector memory T-cell pool, memory B cells and the recently described population of tissue resident memory cells (TRM). The cellular origin of TRM CD4 cells is unknown and the contribution of this CD4 memory population to host defense still remains elusive. By using IL-17A tracking-fate-mouse models we found that a significant fraction of the CD4 TRM cells derive from IL-17A producing effector (TH17) cells following primary immunization. Maintenance of these resting exTH17 TRM cells is mediated by IL-7, produced by lymphatic endothelial cells. During a memory response, we show that neither antibodies, nor gd T cells, nor circulatory memory T cells are sufficient for the rapid host defense required to eliminate the pathogen. Using parabiosis and depletion studies, we demonstrated that CD4 exTH17 TRM cells play an important role in respiratory defense and bacterial clearance. Upon infection, exTH17 TRM cells rapidly produce IL-17A and IFN-γ to promote neutrophil infiltration and bacterial clearance. These studies delineate the origin, function and importance of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design, which is especially imperative for those pathogens that are resistant to antibiotic treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE131450 | GEO | 2019/05/21

REPOSITORIES: GEO

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Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection

Project description:Mucosal barrier surfaces serve as the critical first line of defense separating our bodies from the plethora of pathogenic microorganisms that inhabit our environment. Adaptive immunity provides life-long protection through the generation of a central and effector memory T-cell pool, memory B cells and the recently described population of tissue resident memory cells (TRM). The cellular origin of TRM CD4 cells is unknown and the contribution of this CD4 memory population to host defense still remains elusive. By using IL-17A tracking-fate-mouse models we found that a significant fraction of the CD4 TRM cells derive from IL-17A producing effector (TH17) cells following primary immunization. Maintenance of these resting exTH17 TRM cells is mediated by IL-7, produced by lymphatic endothelial cells. During a memory response, we show that neither antibodies, nor gd T cells, nor circulatory memory T cells are sufficient for the rapid host defense required to eliminate the pathogen. Using parabiosis and depletion studies, we demonstrated that CD4 exTH17 TRM cells play an important role in respiratory defense and bacterial clearance. Upon infection, exTH17 TRM cells rapidly produce IL-17A and IFN-γ to promote neutrophil infiltration and bacterial clearance. These studies delineate the origin, function and importance of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design, which is especially imperative for those pathogens that are resistant to antibiotic treatment.

2019-04-30 | GSE130446 | GEO

Microarray gene expression data from sorted lung epithelial cells during heterotypic immunity

Project description:Previous pneumococcal experience establishes lung-resident IL-17A-producing CD4+ memory TRM cells that accelerate neutrophil recruitment against heterotypic pneumococci. Herein, we unravel a novel crosstalk between CD4+ TRM cells and lung epithelial cells underlying this protective immunity. Genome-wide expression analyses of lung epithelial cells in CD4+ cell sufficient and CD4+ cell deficient heterotypic immune murine lungs revealed a significant remodeling of the epithelial transcriptome of infected lungs due to infection history, ~80% of which was CD4+ cell-dependent.

2020-03-16 | GSE128897 | GEO

B cell presentation of Chlamydia antigen selects out protective CD4ɣ13 T cells; implications for genital tract tissue resident memory lymphocyte clusters

Project description:Surveillance and defense of the enormous mucosal interface with the nonsterile world is critical to protecting the host from a wide range of pathogens. Chlamydia trachomatis (Ct) is an intracellular bacterial pathogen that replicates almost exclusively in the epithelium of the reproductive tract. The fallopian tubes and vagina seem poorly suited to surveillance and defense as they have limited immune infrastructure positioned near the epithelium. However, a dynamic process during clearing primary infections leaves behind new immune infrastructure positioned near epithelium. Memory lymphocyte clusters (MLC) harboring tissue resident memory T cells (TRM) are presumed to play an important role in protection from subsequent infections. Histologically Chlamydia MLC appear to be based on B cells. We therefore investigated B cell populations in the murine genital tract post-clearance of C. muridarum infections and the nature of T cells recovered from immune mice using immune B cells as antigen presenting cells (APC). These studies revealed a plasma B cell population in the genital tract consistent with histopathology seen in mouse and human Chlamydia infections, and discovery of a novel CD4 T cell subset based on production of IFN-ɣ and IL-13. We discuss these results in the context of Trm and previously published data showing that in humans a peripheral blood mononuclear IL-13 response to elementary bodies (EB) predicts resistance to future infection.

2017-12-01 | GSE104743 | GEO

Heterogeneous maintenance of human tissue resident memory T cells based on efflux capacities

Project description:Tissue-resident memory T cells (TRM) accelerate pathogen clearance through rapid and enhanced functional responses in situ. In humans, TRM cells are prevalent in diverse anatomic sites throughout the human lifespan, yet mechanisms for long-term maintenance are unknown. Here, we identify subpopulations of human TRM in mucosal and lymphoid sites based on differential efflux of mitochondrial dyes, with distinct transcriptional profiles, turnover, and functional capacities. TRM are enriched in efflux(+) populations compared with circulating memory CD8+T cells. Compared to efflux- TRM, efflux(+) TRM showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling to homeostatic cytokines. Moreover, efflux(+) and efflux(-) TRM subsets both maintain TRM characteristics when activated, while efflux(+) TRM produce IL-17 and efflux(-) produce higher levels of IFN-γ and IL-2. Our results suggest a model for cooperative maintenance of T cell immunity in tissues through interplay of subsets with complementary capacities for longevity and effector function.

2018-12-26 | GSE109841 | GEO

Corral2021 - Interplay between SMAD2 and STAT5A regulating IL-17A/F expression in Th cells.

Project description:IL-17A and F are critical cytokines in anti-microbial immunity but also contribute to auto-immune pathologies. Recent evidence suggests that they may be differentially produced by T-helper (Th) cells but the underlying mechanisms remain unknown. To address this question, a logical model containing 82 components and 136 regulatory links was developed and calibrated with original flow cytometry data using naive CD4+ T cells in conditions inducing either IL-17A or F. Model analyses led to the identification of the transcription factors NFAT2A, STAT5A and Smad2 as key components explaining the differential expression of IL-17A and IL-17F, with STAT5A controlling IL-17F expression, and an interplay of NFAT2A, STAT5A and Smad2 controlling IL-17A expression.

2021-04-06 | MODEL2101150001 | BioModels

Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy subjects

Project description:Tissue-resident memory T cells (TRM) persist locally in non-lymphoid tissues where they provide front-line defense against recurring insults. TRM at barrier surfaces express the markers CD103 and/or CD69 which function to retain them in epithelial tissues. In humans, neither the long-term migratory behavior of TRM nor their ability to re-enter the circulation and potentially migrate to distant tissue sites have been investigated. Using tissue explant cultures, we found that CD4+CD69+CD103+ TRM in human skin can downregulate CD69 and exit the tissue. Additionally, we identified a skin-tropic CD4+CD69-CD103+ population in human lymph and blood that is transcriptionally, functionally and clonally related to the CD4+CD69+CD103+ TRM population in the skin. Using a skin xenograft model, we confirmed that a fraction of the human cutaneous CD4+CD103+ TRM population can re-enter circulation, and migrate to secondary human skin sites where they re-assume a TRM phenotype. Thus, our data challenge current concepts regarding the strict tissue compartmentalization of CD4+ T cell memory in humans.

2019-05-25 | GSE131770 | GEO

Single cell CITE-seq and VDJ sequencing of CD8+ central memory blood T cells (TCM) and their in-vivo matured tissue-resident memory-like T cells (TRM)

Project description:The aim of the experiment was to understand the clonal relationship between CD8+ central memory blood T cells (TCM) and the in-vivo matured TCM tissue-resident memory-like T cells (TRM) on day 14. TCM were FACS sorted from human PBMCs (n=5). Half of the cells were processed on day 1 and half of the cells of each donor were matured into TRM with anti-CD3, IL-15 and TGF beta for 14 days. Both day 1 TCM and matured day 14 TRM-like cells were further processed using the 5´10X genomics workflow.

2023-06-12 | E-MTAB-12840 | biostudies-arrayexpress

RNA-Seq of wild-type CD4+ T cell subsets during LCMV infection

Project description:Following an infection, CD4+ lymphocytes can differentiate into long-lived memory T cells, some of which circulate through the secondary lymphoid organs (SLOs) while a population lodges in non-lymphoid tissues. While CD4+ T cells in SLOs have been examined, the developmental origins and transcriptional regulation of tissue-resident memory T cells (TRM) remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profile of virus-specific CD4+ TRM in the small intestine (SI) following acute lymphocytic choriomeningitis virus (LCMV) infection. LCMV-specific CD4+ TRM at day 7 of infection shared a gene-expression program and chromatin profile with TH1 cells and progressively acquired a mature TRM program by day 21 memory time point, supporting a developmental relationship between TRM and TH1 subsets. Furthermore, we demonstrated that TRM cells expressed genes associated with both effector and memory T cell fates, including the transcriptional regulators Blimp1, Id2, and Bcl6 which were necessary for CD4+ TRM differentiation. TH1-associated Blimp1 and Id2 were both required for early TRM formation, while TFH-associated Bcl6 initially inhibited TRM differentiation but was critical for development of long-lived TRM cells. Our results identify new significance for TFs previously associated with circulating CD4+ T cell populations and their roles in driving SI CD4+ TRM differentiation.

2023-06-30 | GSE184262 | GEO

ATAC-Seq of CD4+ T cell subsets during LCMV infection

2023-06-30 | GSE184260 | GEO

Single-cell RNA-Seq of wild-type and Bcl6KO CD4+ T cell subsets during LCMV infection

2023-06-30 | GSE184259 | GEO