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TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8(+) T-cell homeostasis
Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metab...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719877/ https://www.ncbi.nlm.nih.gov/pubmed/31433805 http://dx.doi.org/10.1371/journal.pbio.3000420 |
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author | Shi, Lei Chen, Xia Zang, Aiping Li, Tiantian Hu, Yanxiang Ma, Shixin Lü, Mengdie Yin, Huiyong Wang, Haikun Zhang, Xiaoming Zhang, Bei Leng, Qibin Yang, Jinbo Xiao, Hui |
author_facet | Shi, Lei Chen, Xia Zang, Aiping Li, Tiantian Hu, Yanxiang Ma, Shixin Lü, Mengdie Yin, Huiyong Wang, Haikun Zhang, Xiaoming Zhang, Bei Leng, Qibin Yang, Jinbo Xiao, Hui |
author_sort | Shi, Lei |
collection | PubMed |
description | Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic–epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. Specific ablation of Tsc1 in the DC compartment (Tsc1(DC-KO)) largely preserved DC development but led to pronounced reduction in naïve and memory–phenotype cluster of differentiation (CD)8(+) T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. Moreover, Tsc1(DC-KO) mice were unable to launch efficient antigen-specific CD8(+) T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification. |
format | Online Article Text |
id | pubmed-6719877 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-67198772019-09-10 TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8(+) T-cell homeostasis Shi, Lei Chen, Xia Zang, Aiping Li, Tiantian Hu, Yanxiang Ma, Shixin Lü, Mengdie Yin, Huiyong Wang, Haikun Zhang, Xiaoming Zhang, Bei Leng, Qibin Yang, Jinbo Xiao, Hui PLoS Biol Research Article Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic–epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. Specific ablation of Tsc1 in the DC compartment (Tsc1(DC-KO)) largely preserved DC development but led to pronounced reduction in naïve and memory–phenotype cluster of differentiation (CD)8(+) T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. Moreover, Tsc1(DC-KO) mice were unable to launch efficient antigen-specific CD8(+) T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification. Public Library of Science 2019-08-21 /pmc/articles/PMC6719877/ /pubmed/31433805 http://dx.doi.org/10.1371/journal.pbio.3000420 Text en © 2019 Shi et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Shi, Lei Chen, Xia Zang, Aiping Li, Tiantian Hu, Yanxiang Ma, Shixin Lü, Mengdie Yin, Huiyong Wang, Haikun Zhang, Xiaoming Zhang, Bei Leng, Qibin Yang, Jinbo Xiao, Hui TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8(+) T-cell homeostasis |
title | TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8(+) T-cell homeostasis |
title_full | TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8(+) T-cell homeostasis |
title_fullStr | TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8(+) T-cell homeostasis |
title_full_unstemmed | TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8(+) T-cell homeostasis |
title_short | TSC1/mTOR-controlled metabolic–epigenetic cross talk underpins DC control of CD8(+) T-cell homeostasis |
title_sort | tsc1/mtor-controlled metabolic–epigenetic cross talk underpins dc control of cd8(+) t-cell homeostasis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719877/ https://www.ncbi.nlm.nih.gov/pubmed/31433805 http://dx.doi.org/10.1371/journal.pbio.3000420 |
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