Homeostatic control of metabolic and functional fitness of T reg cells by LKB1 signalling
Regulatory T cells (T cells) have a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis. Transcriptional programming of regulatory mechanisms facilitates the functional activation of T cells in the prevention of diverse types of inflammatory responses. I...
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Veröffentlicht in: | Nature (London) 2017-08, Vol.548 (7669), p.602 |
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container_title | Nature (London) |
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creator | Yang, Kai Blanco, Daniel Bastardo Neale, Geoffrey Vogel, Peter Avila, Julian Clish, Clary B Wu, Chuan Shrestha, Sharad Rankin, Sherri Long, Lingyun Kc, Anil Chi, Hongbo |
description | Regulatory T cells (T
cells) have a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis. Transcriptional programming of regulatory mechanisms facilitates the functional activation of T
cells in the prevention of diverse types of inflammatory responses. It remains unclear how T
cells orchestrate their homeostasis and interplay with environmental signals. Here we show that liver kinase B1 (LKB1) programs the metabolic and functional fitness of T
cells in the control of immune tolerance and homeostasis. Mice with a T
-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive T
2-type-dominant responses. LKB1 deficiency disrupted T
cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1 and the TNF receptor superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in T
cells was independent of conventional AMPK signalling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signalling for the control of PD-1 and TNF receptor proteins. Blockade of PD-1 activity reinvigorated the ability of LKB1-deficient T
cells to suppress T
2 responses and the interplay with dendritic cells primed by thymic stromal lymphopoietin. Thus, T
cells use LKB1 signalling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance. |
doi_str_mv | 10.1038/nature23665 |
format | Article |
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cells) have a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis. Transcriptional programming of regulatory mechanisms facilitates the functional activation of T
cells in the prevention of diverse types of inflammatory responses. It remains unclear how T
cells orchestrate their homeostasis and interplay with environmental signals. Here we show that liver kinase B1 (LKB1) programs the metabolic and functional fitness of T
cells in the control of immune tolerance and homeostasis. Mice with a T
-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive T
2-type-dominant responses. LKB1 deficiency disrupted T
cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1 and the TNF receptor superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in T
cells was independent of conventional AMPK signalling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signalling for the control of PD-1 and TNF receptor proteins. Blockade of PD-1 activity reinvigorated the ability of LKB1-deficient T
cells to suppress T
2 responses and the interplay with dendritic cells primed by thymic stromal lymphopoietin. Thus, T
cells use LKB1 signalling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance.</description><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature23665</identifier><identifier>PMID: 28847007</identifier><language>eng</language><publisher>England</publisher><subject>Animals ; Apoptosis ; beta Catenin - metabolism ; Cell Survival - genetics ; Cytokines - metabolism ; Dendritic Cells - immunology ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Glucocorticoid-Induced TNFR-Related Protein - metabolism ; Homeostasis ; Immune Tolerance ; Mice ; Mitochondria - metabolism ; Mitochondria - pathology ; Programmed Cell Death 1 Receptor - antagonists & inhibitors ; Programmed Cell Death 1 Receptor - biosynthesis ; Programmed Cell Death 1 Receptor - metabolism ; Protein-Serine-Threonine Kinases - deficiency ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Receptors, OX40 - metabolism ; Receptors, Tumor Necrosis Factor - metabolism ; Signal Transduction ; T-Lymphocytes, Regulatory - cytology ; T-Lymphocytes, Regulatory - immunology ; T-Lymphocytes, Regulatory - metabolism ; Th2 Cells - immunology</subject><ispartof>Nature (London), 2017-08, Vol.548 (7669), p.602</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28847007$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Kai</creatorcontrib><creatorcontrib>Blanco, Daniel Bastardo</creatorcontrib><creatorcontrib>Neale, Geoffrey</creatorcontrib><creatorcontrib>Vogel, Peter</creatorcontrib><creatorcontrib>Avila, Julian</creatorcontrib><creatorcontrib>Clish, Clary B</creatorcontrib><creatorcontrib>Wu, Chuan</creatorcontrib><creatorcontrib>Shrestha, Sharad</creatorcontrib><creatorcontrib>Rankin, Sherri</creatorcontrib><creatorcontrib>Long, Lingyun</creatorcontrib><creatorcontrib>Kc, Anil</creatorcontrib><creatorcontrib>Chi, Hongbo</creatorcontrib><title>Homeostatic control of metabolic and functional fitness of T reg cells by LKB1 signalling</title><title>Nature (London)</title><addtitle>Nature</addtitle><description>Regulatory T cells (T
cells) have a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis. Transcriptional programming of regulatory mechanisms facilitates the functional activation of T
cells in the prevention of diverse types of inflammatory responses. It remains unclear how T
cells orchestrate their homeostasis and interplay with environmental signals. Here we show that liver kinase B1 (LKB1) programs the metabolic and functional fitness of T
cells in the control of immune tolerance and homeostasis. Mice with a T
-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive T
2-type-dominant responses. LKB1 deficiency disrupted T
cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1 and the TNF receptor superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in T
cells was independent of conventional AMPK signalling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signalling for the control of PD-1 and TNF receptor proteins. Blockade of PD-1 activity reinvigorated the ability of LKB1-deficient T
cells to suppress T
2 responses and the interplay with dendritic cells primed by thymic stromal lymphopoietin. Thus, T
cells use LKB1 signalling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>beta Catenin - metabolism</subject><subject>Cell Survival - genetics</subject><subject>Cytokines - metabolism</subject><subject>Dendritic Cells - immunology</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Glucocorticoid-Induced TNFR-Related Protein - metabolism</subject><subject>Homeostasis</subject><subject>Immune Tolerance</subject><subject>Mice</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Programmed Cell Death 1 Receptor - antagonists & inhibitors</subject><subject>Programmed Cell Death 1 Receptor - biosynthesis</subject><subject>Programmed Cell Death 1 Receptor - metabolism</subject><subject>Protein-Serine-Threonine Kinases - deficiency</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Receptors, OX40 - metabolism</subject><subject>Receptors, Tumor Necrosis Factor - metabolism</subject><subject>Signal Transduction</subject><subject>T-Lymphocytes, Regulatory - cytology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>T-Lymphocytes, Regulatory - metabolism</subject><subject>Th2 Cells - immunology</subject><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1j8FKxDAURYMgzji6ci_5gWrSpE261EFnxIKbblwNr-lLqaRJadLF_L0VdXXhcjjcS8gdZw-cCf3oIS0z5qIsiwuy5VKVmSy12pDrGL8YYwVX8opscq2lYkxtyecxjBhigjQYaoJPc3A0WDpigja4tQTfUbt4k4bgwVE7JI8x_jANnbGnBp2LtD3T-v2Z0zj0K-UG39-QSwsu4u1f7kjz-tLsj1n9cXjbP9XZVImUmU6i1RJArluL0nINRoNQFRrQysgqZ5VuqxY1A1sUClFY3UqpK9sZmxdiR-5_tdPSjtidpnkYYT6f_i-KbwfhUpo</recordid><startdate>20170831</startdate><enddate>20170831</enddate><creator>Yang, Kai</creator><creator>Blanco, Daniel Bastardo</creator><creator>Neale, Geoffrey</creator><creator>Vogel, Peter</creator><creator>Avila, Julian</creator><creator>Clish, Clary B</creator><creator>Wu, Chuan</creator><creator>Shrestha, Sharad</creator><creator>Rankin, Sherri</creator><creator>Long, Lingyun</creator><creator>Kc, Anil</creator><creator>Chi, Hongbo</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20170831</creationdate><title>Homeostatic control of metabolic and functional fitness of T reg cells by LKB1 signalling</title><author>Yang, Kai ; Blanco, Daniel Bastardo ; Neale, Geoffrey ; Vogel, Peter ; Avila, Julian ; Clish, Clary B ; Wu, Chuan ; Shrestha, Sharad ; Rankin, Sherri ; Long, Lingyun ; Kc, Anil ; Chi, Hongbo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p93t-cd4ef84aa447656f18ac8a379eca87c492098b9be80af557ee3f8b4489fdcf253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>beta Catenin - metabolism</topic><topic>Cell Survival - genetics</topic><topic>Cytokines - metabolism</topic><topic>Dendritic Cells - immunology</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Glucocorticoid-Induced TNFR-Related Protein - metabolism</topic><topic>Homeostasis</topic><topic>Immune Tolerance</topic><topic>Mice</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondria - pathology</topic><topic>Programmed Cell Death 1 Receptor - antagonists & inhibitors</topic><topic>Programmed Cell Death 1 Receptor - biosynthesis</topic><topic>Programmed Cell Death 1 Receptor - metabolism</topic><topic>Protein-Serine-Threonine Kinases - deficiency</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Receptors, OX40 - metabolism</topic><topic>Receptors, Tumor Necrosis Factor - metabolism</topic><topic>Signal Transduction</topic><topic>T-Lymphocytes, Regulatory - cytology</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>T-Lymphocytes, Regulatory - metabolism</topic><topic>Th2 Cells - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Kai</creatorcontrib><creatorcontrib>Blanco, Daniel Bastardo</creatorcontrib><creatorcontrib>Neale, Geoffrey</creatorcontrib><creatorcontrib>Vogel, Peter</creatorcontrib><creatorcontrib>Avila, Julian</creatorcontrib><creatorcontrib>Clish, Clary B</creatorcontrib><creatorcontrib>Wu, Chuan</creatorcontrib><creatorcontrib>Shrestha, Sharad</creatorcontrib><creatorcontrib>Rankin, Sherri</creatorcontrib><creatorcontrib>Long, Lingyun</creatorcontrib><creatorcontrib>Kc, Anil</creatorcontrib><creatorcontrib>Chi, Hongbo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Kai</au><au>Blanco, Daniel Bastardo</au><au>Neale, Geoffrey</au><au>Vogel, Peter</au><au>Avila, Julian</au><au>Clish, Clary B</au><au>Wu, Chuan</au><au>Shrestha, Sharad</au><au>Rankin, Sherri</au><au>Long, Lingyun</au><au>Kc, Anil</au><au>Chi, Hongbo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Homeostatic control of metabolic and functional fitness of T reg cells by LKB1 signalling</atitle><jtitle>Nature (London)</jtitle><addtitle>Nature</addtitle><date>2017-08-31</date><risdate>2017</risdate><volume>548</volume><issue>7669</issue><spage>602</spage><pages>602-</pages><eissn>1476-4687</eissn><abstract>Regulatory T cells (T
cells) have a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis. Transcriptional programming of regulatory mechanisms facilitates the functional activation of T
cells in the prevention of diverse types of inflammatory responses. It remains unclear how T
cells orchestrate their homeostasis and interplay with environmental signals. Here we show that liver kinase B1 (LKB1) programs the metabolic and functional fitness of T
cells in the control of immune tolerance and homeostasis. Mice with a T
-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive T
2-type-dominant responses. LKB1 deficiency disrupted T
cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1 and the TNF receptor superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in T
cells was independent of conventional AMPK signalling or the mTORC1-HIF-1α axis, but contributed to the activation of β-catenin signalling for the control of PD-1 and TNF receptor proteins. Blockade of PD-1 activity reinvigorated the ability of LKB1-deficient T
cells to suppress T
2 responses and the interplay with dendritic cells primed by thymic stromal lymphopoietin. Thus, T
cells use LKB1 signalling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance.</abstract><cop>England</cop><pmid>28847007</pmid><doi>10.1038/nature23665</doi></addata></record> |
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subjects | Animals Apoptosis beta Catenin - metabolism Cell Survival - genetics Cytokines - metabolism Dendritic Cells - immunology Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Glucocorticoid-Induced TNFR-Related Protein - metabolism Homeostasis Immune Tolerance Mice Mitochondria - metabolism Mitochondria - pathology Programmed Cell Death 1 Receptor - antagonists & inhibitors Programmed Cell Death 1 Receptor - biosynthesis Programmed Cell Death 1 Receptor - metabolism Protein-Serine-Threonine Kinases - deficiency Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Receptors, OX40 - metabolism Receptors, Tumor Necrosis Factor - metabolism Signal Transduction T-Lymphocytes, Regulatory - cytology T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism Th2 Cells - immunology |
title | Homeostatic control of metabolic and functional fitness of T reg cells by LKB1 signalling |
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