Cutting Edge: TGF-β and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets
Murine Foxp3 regulatory T cells (Tregs) differentiated in vitro (induced Tregs [iTregs]) in the presence of anti-inflammatory cytokine TGF-β rely predominantly upon lipid oxidation to fuel mitochondrial oxidative phosphorylation. Foxp3 expression underlies this metabolic preference, as it suppresses...
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| Veröffentlicht in: | The Journal of immunology (1950) 2018-10, Vol.201 (8), p.2215-2219 |
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| container_title | The Journal of immunology (1950) |
| container_volume | 201 |
| creator | Priyadharshini, Bhavana Loschi, Michael Newton, Ryan H Zhang, Jian-Wen Finn, Kelsey K Gerriets, Valerie A Huynh, Alexandria Rathmell, Jeffery C Blazar, Bruce R Turka, Laurence A |
| description | Murine Foxp3
regulatory T cells (Tregs) differentiated in vitro (induced Tregs [iTregs]) in the presence of anti-inflammatory cytokine TGF-β rely predominantly upon lipid oxidation to fuel mitochondrial oxidative phosphorylation. Foxp3 expression underlies this metabolic preference, as it suppresses glycolysis and drives oxidative phosphorylation. In this study, we show that in contrast to iTregs, thymic-derived Tregs (tTregs), engage in glycolysis and glutaminolysis at levels comparable to effector T cells despite maintained Foxp3 expression. Interestingly, exposure of tTregs to the anti-inflammatory cytokine TGF-β represses PI3K-mediated mTOR signaling, inhibits glucose transporter and
expression, and reprograms their metabolism to favor oxidative phosphorylation. Conversely, replicating the effects of inflammation via elevation of PI3K signaling has minimal effects on tTregs but dramatically enhances the glycolysis of normally oxidative iTregs, resulting in reduction of Foxp3 expression. Collectively, these findings suggest both extrinsic and intrinsic factors govern the unique metabolic signature of Treg subsets. |
| doi_str_mv | 10.4049/jimmunol.1800311 |
| format | Article |
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regulatory T cells (Tregs) differentiated in vitro (induced Tregs [iTregs]) in the presence of anti-inflammatory cytokine TGF-β rely predominantly upon lipid oxidation to fuel mitochondrial oxidative phosphorylation. Foxp3 expression underlies this metabolic preference, as it suppresses glycolysis and drives oxidative phosphorylation. In this study, we show that in contrast to iTregs, thymic-derived Tregs (tTregs), engage in glycolysis and glutaminolysis at levels comparable to effector T cells despite maintained Foxp3 expression. Interestingly, exposure of tTregs to the anti-inflammatory cytokine TGF-β represses PI3K-mediated mTOR signaling, inhibits glucose transporter and
expression, and reprograms their metabolism to favor oxidative phosphorylation. Conversely, replicating the effects of inflammation via elevation of PI3K signaling has minimal effects on tTregs but dramatically enhances the glycolysis of normally oxidative iTregs, resulting in reduction of Foxp3 expression. Collectively, these findings suggest both extrinsic and intrinsic factors govern the unique metabolic signature of Treg subsets.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1800311</identifier><identifier>PMID: 30209190</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Cell Differentiation ; Cells, Cultured ; Cellular Reprogramming ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Glycolysis ; Immunomodulation ; Lymphocyte Activation ; Mice ; Mice, Transgenic ; Oxidative Phosphorylation ; Phosphatidylinositol 3-Kinase - metabolism ; Signal Transduction ; T-Lymphocyte Subsets - immunology ; T-Lymphocytes, Regulatory - immunology ; Thymus Gland - physiology ; TOR Serine-Threonine Kinases - metabolism ; Transforming Growth Factor beta - metabolism</subject><ispartof>The Journal of immunology (1950), 2018-10, Vol.201 (8), p.2215-2219</ispartof><rights>Copyright © 2018 by The American Association of Immunologists, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c341t-323587dead7ea667ecfb377619461a1f088ec041bfa210576f6b7fd2ab9c586d3</citedby><cites>FETCH-LOGICAL-c341t-323587dead7ea667ecfb377619461a1f088ec041bfa210576f6b7fd2ab9c586d3</cites><orcidid>0000-0003-0995-1294 ; 0000-0002-9608-9841 ; 0000-0003-3787-218X ; 0000-0002-1553-2590</orcidid></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/30209190$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Priyadharshini, Bhavana</creatorcontrib><creatorcontrib>Loschi, Michael</creatorcontrib><creatorcontrib>Newton, Ryan H</creatorcontrib><creatorcontrib>Zhang, Jian-Wen</creatorcontrib><creatorcontrib>Finn, Kelsey K</creatorcontrib><creatorcontrib>Gerriets, Valerie A</creatorcontrib><creatorcontrib>Huynh, Alexandria</creatorcontrib><creatorcontrib>Rathmell, Jeffery C</creatorcontrib><creatorcontrib>Blazar, Bruce R</creatorcontrib><creatorcontrib>Turka, Laurence A</creatorcontrib><title>Cutting Edge: TGF-β and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Murine Foxp3
regulatory T cells (Tregs) differentiated in vitro (induced Tregs [iTregs]) in the presence of anti-inflammatory cytokine TGF-β rely predominantly upon lipid oxidation to fuel mitochondrial oxidative phosphorylation. Foxp3 expression underlies this metabolic preference, as it suppresses glycolysis and drives oxidative phosphorylation. In this study, we show that in contrast to iTregs, thymic-derived Tregs (tTregs), engage in glycolysis and glutaminolysis at levels comparable to effector T cells despite maintained Foxp3 expression. Interestingly, exposure of tTregs to the anti-inflammatory cytokine TGF-β represses PI3K-mediated mTOR signaling, inhibits glucose transporter and
expression, and reprograms their metabolism to favor oxidative phosphorylation. Conversely, replicating the effects of inflammation via elevation of PI3K signaling has minimal effects on tTregs but dramatically enhances the glycolysis of normally oxidative iTregs, resulting in reduction of Foxp3 expression. Collectively, these findings suggest both extrinsic and intrinsic factors govern the unique metabolic signature of Treg subsets.</description><subject>Animals</subject><subject>Cell Differentiation</subject><subject>Cells, Cultured</subject><subject>Cellular Reprogramming</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Glycolysis</subject><subject>Immunomodulation</subject><subject>Lymphocyte Activation</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Oxidative Phosphorylation</subject><subject>Phosphatidylinositol 3-Kinase - metabolism</subject><subject>Signal Transduction</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Thymus Gland - physiology</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Transforming Growth Factor beta - metabolism</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kLFOwzAURS0EoqWwMyGPLCnPcWInbCi0BdEKRMscObGTukriEjsS_S0-hG8iVQvTG-69R08HoWsC4wCC-G6j67prTDUmEQAl5AQNSRiCxxiwUzQE8H2PcMYH6MLaDQAw8INzNKDgQ0xiGKKvpHNONyWeyFLd49Vs6v18Y9FI_LY2drsWTstdpRtjtTMVpt6LboRVeKnLRlQWL4zsKuEUftS25-QOL5QTmam0rbEp8Lsq97lpd3iFE1VVeNllVjl7ic6KHqCujneEPqaTVfLkzV9nz8nD3MtpQJxHfRpGXCohuRKMcZUXGeWckThgRJACokjlEJCsED6BkLOCZbyQvsjiPIyYpCN0e-BuW_PZKevSWtu8f0Q0ynQ27VeU8ZDG0FfhUM1bY22rinTb6lq0u5RAuved_vlOj777yc2R3mW1kv-DP8H0Fz-Xfyg</recordid><startdate>20181015</startdate><enddate>20181015</enddate><creator>Priyadharshini, Bhavana</creator><creator>Loschi, Michael</creator><creator>Newton, Ryan H</creator><creator>Zhang, Jian-Wen</creator><creator>Finn, Kelsey K</creator><creator>Gerriets, Valerie A</creator><creator>Huynh, Alexandria</creator><creator>Rathmell, Jeffery C</creator><creator>Blazar, Bruce R</creator><creator>Turka, Laurence A</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0995-1294</orcidid><orcidid>https://orcid.org/0000-0002-9608-9841</orcidid><orcidid>https://orcid.org/0000-0003-3787-218X</orcidid><orcidid>https://orcid.org/0000-0002-1553-2590</orcidid></search><sort><creationdate>20181015</creationdate><title>Cutting Edge: TGF-β and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets</title><author>Priyadharshini, Bhavana ; Loschi, Michael ; Newton, Ryan H ; Zhang, Jian-Wen ; Finn, Kelsey K ; Gerriets, Valerie A ; Huynh, Alexandria ; Rathmell, Jeffery C ; Blazar, Bruce R ; Turka, Laurence A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c341t-323587dead7ea667ecfb377619461a1f088ec041bfa210576f6b7fd2ab9c586d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Cell Differentiation</topic><topic>Cells, Cultured</topic><topic>Cellular Reprogramming</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Glycolysis</topic><topic>Immunomodulation</topic><topic>Lymphocyte Activation</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Oxidative Phosphorylation</topic><topic>Phosphatidylinositol 3-Kinase - metabolism</topic><topic>Signal Transduction</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Thymus Gland - physiology</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Transforming Growth Factor beta - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Priyadharshini, Bhavana</creatorcontrib><creatorcontrib>Loschi, Michael</creatorcontrib><creatorcontrib>Newton, Ryan H</creatorcontrib><creatorcontrib>Zhang, Jian-Wen</creatorcontrib><creatorcontrib>Finn, Kelsey K</creatorcontrib><creatorcontrib>Gerriets, Valerie A</creatorcontrib><creatorcontrib>Huynh, Alexandria</creatorcontrib><creatorcontrib>Rathmell, Jeffery C</creatorcontrib><creatorcontrib>Blazar, Bruce R</creatorcontrib><creatorcontrib>Turka, Laurence A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Priyadharshini, Bhavana</au><au>Loschi, Michael</au><au>Newton, Ryan H</au><au>Zhang, Jian-Wen</au><au>Finn, Kelsey K</au><au>Gerriets, Valerie A</au><au>Huynh, Alexandria</au><au>Rathmell, Jeffery C</au><au>Blazar, Bruce R</au><au>Turka, Laurence A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cutting Edge: TGF-β and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2018-10-15</date><risdate>2018</risdate><volume>201</volume><issue>8</issue><spage>2215</spage><epage>2219</epage><pages>2215-2219</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Murine Foxp3
regulatory T cells (Tregs) differentiated in vitro (induced Tregs [iTregs]) in the presence of anti-inflammatory cytokine TGF-β rely predominantly upon lipid oxidation to fuel mitochondrial oxidative phosphorylation. Foxp3 expression underlies this metabolic preference, as it suppresses glycolysis and drives oxidative phosphorylation. In this study, we show that in contrast to iTregs, thymic-derived Tregs (tTregs), engage in glycolysis and glutaminolysis at levels comparable to effector T cells despite maintained Foxp3 expression. Interestingly, exposure of tTregs to the anti-inflammatory cytokine TGF-β represses PI3K-mediated mTOR signaling, inhibits glucose transporter and
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| subjects | Animals Cell Differentiation Cells, Cultured Cellular Reprogramming Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Glycolysis Immunomodulation Lymphocyte Activation Mice Mice, Transgenic Oxidative Phosphorylation Phosphatidylinositol 3-Kinase - metabolism Signal Transduction T-Lymphocyte Subsets - immunology T-Lymphocytes, Regulatory - immunology Thymus Gland - physiology TOR Serine-Threonine Kinases - metabolism Transforming Growth Factor beta - metabolism |
| title | Cutting Edge: TGF-β and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets |
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