Similar Datasets
Project description:TGF-beta signaling is required for the differentiation of gut-resident memory CD8 T cells. Here, we showed that the deficiency of transcription factor T-bet partially rescued the differentiation of TGF-beta receptor deficient gut-resident memory CD8 T cells.
2021-10-06 | GSE184628 | GEO
Project description:TGF-beta signaling is required for the differentiation of gut-resident memory CD8 T cells. Here, we showed that the deficiency of transcription factor T-bet partially rescued the differentiation of TGF-beta receptor deficient gut-resident memory CD8 T cells.
2021-10-06 | GSE184627 | GEO
Project description:T-bet Suppresses TGF-b-independent Gut-resident Memory CD8+ T Cell Differentiation.
| PRJNA765387 | ENA
Project description:T-bet Suppresses TGF-b-independent Gut-resident Memory CD8+ T Cell Differentiation [RNA-seq]
| PRJNA765390 | ENA
Project description:T-bet Suppresses TGF-b-independent Gut-resident Memory CD8+ T Cell Differentiation [ATAC-seq]
| PRJNA765391 | ENA
Project description:Resident Memory T cells (TRM) play a vital role in regional immune defense in barrier organs. Although laboratory rodents have been extensively used to study fundamental TRM biology, poor isolation efficiency, sampling bias and low cell survival rates have limited our ability to conduct TRM-focused high-throughput assays. Here, we engineered a murine vaginal epithelial organoid (VEO)-CD8 T cell co-culture system that supports CD8 TRM differentiation in vitro. The three-dimensional VEOs established from murine adult stem cells resembled stratified squamous vaginal epithelium and induced gradual differentiation of activated CD8 T cells into epithelial TRM. These in vitro generated TRM were phenotypically and transcriptionally similar to in vivo TRM, and key tissue residency features were reinforced with a second cognate-antigen exposure during co-culture. TRM differentiation was not affected even when VEOs and CD8 T cells were separated by a semipermeable barrier, indicating soluble factors' involvement. Pharmacological and genetic approaches showed that TGF-β signaling played a crucial role in their differentiation. We found that the VEOs in our model remained susceptible to viral infections and the CD8 T cells were amenable to genetic manipulation; both of which will allow detailed interrogation of antiviral CD8 T cell biology in a reductionist setting. In summary, we established a robust model which captures bonafide TRM differentiation that is scalable, open to iterative sampling, and can be subjected to high throughput assays that will rapidly add to our understanding of TRM.
| S-EPMC10705482 | biostudies-literature
Project description:Transforming growth factor β (TGF-β) represents a well-established signal required for tissue-resident memory T cell (TRM) formation at intestinal surfaces, regulating the expression of a large collection of genes coordinately promoting intestinal TRM differentiation. The functional contribution from each TGF-β-controlled transcription factor is not entirely known. Here, we find that TGF-β-induced T-bet downregulation and Hic1 induction represent two critical events during intestinal TRM differentiation. Importantly, T-bet deficiency significantly rescues intestinal TRM formation in the absence of the TGF-β receptor. Hic1 induction further strengthens TRM maturation in the absence of TGF-β and T-bet. Our results reveal that provision of certain TGF-β-induced molecular events can partially replace TGF-β signaling to promote the establishment of intestinal TRMs, which allows the functional dissection of TGF-β-induced transcriptional targets and molecular mechanisms for TRM differentiation.
| S-EPMC11240284 | biostudies-literature
Project description:Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8+ T cells and self-renewal of central-memory CD8+ T cells. We now show that T-bet represses transcription of IL-7Ralpha and drives differentiation of effector and effector-memory CD8+ T cells at the expense of central-memory cells. We also found T-bet to be overexpressed in CD8+ T cells that differentiated in the absence of CD4+ T cell help, a condition that is associated with defective central-memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of "unhelped" memory CD8+ T cells. T-bet, thus, appears to function as a molecular switch between central- and effector-memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8+ T cells.
| S-EPMC2118697 | biostudies-literature
Project description:IL-15 regulates central and effector memory CD8 T cell (TCM and TEM, respectively) homeostatic proliferation, maintenance, and longevity. Consequently, IL-15 availability hypothetically defines the carrying capacity for total memory CD8 T cells within the host. In conflict with this hypothesis, previous observations demonstrated that boosting generates preternaturally abundant TEM that increases the total quantity of memory CD8 T cells in mice. In this article, we provide a potential mechanistic explanation by reporting that boosted circulating TEM do not require IL-15 for maintenance. We also investigated tissue-resident memory CD8 T cells (TRM), which protect nonlymphoid tissues from reinfection. We observed up to a 50-fold increase in the total magnitude of TRM in mouse mucosal tissues after boosting, suggesting that the memory T cell capacity in tissues is flexible and that TRM may not be under the same homeostatic regulation as primary central memory CD8 T cells and TEM Further analysis identified distinct TRM populations that depended on IL-15 for homeostatic proliferation and survival, depended on IL-15 for homeostatic proliferation but not for survival, or did not depend on IL-15 for either process. These observations on the numerical regulation of T cell memory indicate that there may be significant heterogeneity among distinct TRM populations and also argue against the common perception that developing vaccines that confer protection by establishing abundant TEM and TRM will necessarily erode immunity to previously encountered pathogens as the result of competition for IL-15.
| S-EPMC5145194 | biostudies-literature
Project description:Infection of the central nervous system (CNS) by murine polyomavirus (MuPyV), a persistent natural mouse pathogen, establishes brain-resident memory CD8 T cells (bTRM) that uniformly and chronically express programmed cell death protein 1 (PD-1) irrespective of the expression of αE integrin CD103, a TRM cell marker. In contrast, memory antiviral CD8 T cells in the spleen are PD-1-, despite viral loads being similar in both the brain and spleen during persistent infection. Repetitive antigen engagement is central to sustained PD-1 expression by T cells in chronic viral infections; however, recent evidence indicates that expression of inhibitory receptors, including PD-1, is part of the TRM differentiation program. Here we asked whether PD-1 expression by CD8 bTRM cells during persistent MuPyV encephalitis is antigen dependent. By transferring MuPyV-specific CD8 bTRM cells into the brains of naive mice and mice infected with cognate epitope-sufficient and -deficient MuPyVs, we demonstrate that antigen and inflammation are dispensable for PD-1 maintenance. In vitro and direct ex vivo analyses indicate that CD103- MuPyV-specific CD8 bTRM retain functional competence. We further show that the Pdcd-1 promoter of anti-MuPyV bTRM cells is epigenetically fixed in a demethylated state in the brain. In contrast, the PD-1 promoter of splenic antiviral memory CD8 T cells undergoes remethylation after being demethylated during acute infection. These data show that PD-1 expression is an intrinsic property of brain TRM cells in a persistent CNS viral infection.
| S-EPMC5698165 | biostudies-literature