Retinoic acid and TGF-β orchestrate organ-specific programs of tissue-residency
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE277120 | GEO | 2024/09/16
REPOSITORIES: GEO
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Project description:Tissue-resident memory T (TRM) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common TRM cell fate remains poorly understood. Here, we show that while skin TRM cells strictly require TGF-β for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive the TRM cells in the small intestine.
2024-09-16 | GSE277248 | GEO
Project description:Tissue-resident memory T (TRM) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common TRM cell fate remains poorly understood. Here, we show that while skin TRM cells strictly require TGF-β for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive the TRM cells in the small intestine.
2024-09-16 | GSE277247 | GEO
Project description:Tissue-resident CD8+ memory T (TRM) cells are immune cells that permanently reside at tissue sites where they play an important role in providing rapid protection against reinfection. They are not only phenotypically and functionally distinct from their circulating memory counterparts, but also exhibit a unique transcriptional profile. To date, the local tissue signals required for their development and long-term residency are not well understood. So far, the best-characterised tissue-derived signal is transforming growth factor-β (TGF-β), which has been shown to promote the development of these cells within tissues. In this study, we aimed to determine to what extent the transcriptional signatures of TRM cells from multiple tissues reflects TGF-β imprinting. We activated murine CD8+ T cells, stimulated them in vitro by TGF-β, and profiled their transcriptomes using RNA-seq. Upon comparison, we identified a TGF-β-induced signature of differentially expressed genes between TGF-β-stimulated and -unstimulated cells. Next, we linked this in vitro TGF-β-induced signature to a previously identified in vivo TRM-specific gene set and found considerable (>50%) overlap between the two gene sets, thus showing that a substantial part of the TRM signature can be attributed to TGF-β signalling. Finally, gene set enrichment analysis further revealed that the altered gene signature following TGF-β exposure reflected transcriptional signatures found in TRM cells from both epithelial and non-epithelial tissues. In summary, these findings show that TGF-β has a broad footprint in establishing the residency-specific transcriptional profile of TRM cells, which is detectable in TRM cells from diverse tissues. They further suggest that constitutive TGF-β signaling might be involved for their long-term persistence at tissue sites.
2019-01-23 | GSE125471 | GEO
Project description:Tissue-resident memory T (TRM) cells provide rapid and superior control of localized infections. The transcription factor Runx3 was recently identified as a master regulator of CD8+ T cell tissue residency. However, Runx3 also drives CD8+ T cell lineage commitment and is repressed in CD4+ T cells, raising the possibility that this transcription factor defines a form of tissue residency unique to the CD8+ T cell subset. Here, we show that as a direct consequence of Runx3-deficiency, CD4+ TRM cells in epithelia lack the TGFb-responsive transcriptional network that underpins CD8+ TRM cell residency. Ectopic Runx3 expression in CD4+ T cells rescued this transcriptional program to promote prolonged survival, decreased tissue egress and a microanatomical redistribution towards epithelial layers that combined, resulted in superior local immune protection. Our results thus reveal a mechanistic discordance between CD4+ and CD8+ TRM cell formation in barrier tissues that is controlled by Runx3. Consequently, CD4+ TRM cells are unable to adopt a type of tissue residency that is intrinsically accessible to the CD8+ TRM cell subset.
2022-05-24 | GSE198611 | GEO
Project description:Tissue-resident memory T cells (TRM) are non-recirculating cells that exist throughout the body. While TRM in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here, we chart TRM heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM function, durability and malleability. We find that unequal responsiveness to TGF-β is a major driver of this diversity. Strikingly, dampened TGF-b signaling engendered CD103- TRM with increased proliferative potential, enhanced function, and reduced longevity compared to their TGF-β-responsive CD103+ TRM counterparts. Further, while CD103- TRM readily modified their phenotype upon relocation, CD103+ TRM were comparatively resistant to trans-differentiation. Thus, despite common requirements for TRM development, adaptation of these cells to their tissue of residence confers discrete functional properties such that TRM exist along a spectrum of differentiation potential that is governed by their local microenvironment.
2021-06-24 | GSE178768 | GEO
Project description:Tissue-resident memory T cells (TRM) are non-recirculating cells that exist throughout the body. While TRM in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here, we chart TRM heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM function, durability and malleability. We find that unequal responsiveness to TGF-β is a major driver of this diversity. Strikingly, dampened TGF-b signaling engendered CD103- TRM with increased proliferative potential, enhanced function, and reduced longevity compared to their TGF-β-responsive CD103+ TRM counterparts. Further, while CD103- TRM readily modified their phenotype upon relocation, CD103+ TRM were comparatively resistant to trans-differentiation. Thus, despite common requirements for TRM development, adaptation of these cells to their tissue of residence confers discrete functional properties such that TRM exist along a spectrum of differentiation potential that is governed by their local microenvironment.
2021-06-24 | GSE178767 | GEO
Project description:Tissue-resident memory T cells (TRM) are non-recirculating cells that exist throughout the body. While TRM in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here, we chart TRM heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM function, durability and malleability. We find that unequal responsiveness to TGF-β is a major driver of this diversity. Strikingly, dampened TGF-b signaling engendered CD103- TRM with increased proliferative potential, enhanced function, and reduced longevity compared to their TGF-β-responsive CD103+ TRM counterparts. Further, while CD103- TRM readily modified their phenotype upon relocation, CD103+ TRM were comparatively resistant to trans-differentiation. Thus, despite common requirements for TRM development, adaptation of these cells to their tissue of residence confers discrete functional properties such that TRM exist along a spectrum of differentiation potential that is governed by their local microenvironment.
2021-06-24 | GSE178766 | GEO
Project description:Retinoic acid and TGF-β orchestrate organ-specific programs of tissue-residency
| PRJNA1160824 | ENA
Project description:Tissue-resident memory CD8 T cells (TRM) offer fast, robust, and long-term protection at sites of re-infection1. Tumor-infiltrating lymphocytes (TIL) with characteristics of TRM maintain enhanced effector functions, predict responses to immunotherapy, and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency could inform new approaches to empower T cell responses in tissues and solid tumors. To systematically define the basis for the metabolic reprogramming supporting TRM differentiation, survival, and function, we leveraged in vivo functional genomics, untargeted metabolomics, and transcriptomics of virus-specific memory CD8 T cell populations. We found that memory CD8 T cells deployed a range of adaptations to tissue residency, including a marked reliance on non-steroidal products of the mevalonate/cholesterol pathway, such as Coenzyme Q (CoQ), driven by increased activity of the transcription factor Srebp2. This metabolic adaptation was most pronounced in the small intestine (SI), where TRM interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional TIL in diverse tumor types in mice and humans. Enforcing CoQ synthesis through Fdft1 deletion or Pdss2 overexpression promoted mitochondrial respiration, memory formation upon viral infection, and enhanced antitumor immunity. In sum, through a systematic exploration of TRM metabolism, we reveal how these programs can be leveraged to empower CD8 T cell memory formation in the context of acute infections and enhance antitumor immunity.
2023-07-10 | GSE207043 | GEO
Project description:Tissue-resident memory CD8 T cells (TRM) offer fast, robust, and long-term protection at sites of re-infection1. Tumor-infiltrating lymphocytes (TIL) with characteristics of TRM maintain enhanced effector functions, predict responses to immunotherapy, and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency could inform new approaches to empower T cell responses in tissues and solid tumors. To systematically define the basis for the metabolic reprogramming supporting TRM differentiation, survival, and function, we leveraged in vivo functional genomics, untargeted metabolomics, and transcriptomics of virus-specific memory CD8 T cell populations. We found that memory CD8 T cells deployed a range of adaptations to tissue residency, including a marked reliance on non-steroidal products of the mevalonate/cholesterol pathway, such as Coenzyme Q (CoQ), driven by increased activity of the transcription factor Srebp2. This metabolic adaptation was most pronounced in the small intestine (SI), where TRM interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional TIL in diverse tumor types in mice and humans. Enforcing CoQ synthesis through Fdft1 deletion or Pdss2 overexpression promoted mitochondrial respiration, memory formation upon viral infection, and enhanced antitumor immunity. In sum, through a systematic exploration of TRM metabolism, we reveal how these programs can be leveraged to empower CD8 T cell memory formation in the context of acute infections and enhance antitumor immunity.
2023-07-10 | GSE207042 | GEO