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Peroxisome Proliferator-Activated Receptor-δ Supports the Metabolic Requirements of Cell Growth in TCRβ-Selected Thymocytes and Peripheral CD4 + T Cells
During T cell development, progenitor thymocytes undergo a large proliferative burst immediately following successful TCRβ rearrangement, and defects in genes that regulate this proliferation have a profound effect on thymus cellularity and output. Although the signaling pathways that initiate cell...
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| Published in: | The Journal of immunology (1950) 2018-11, Vol.201 (9), p.2664-2682 |
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| container_issue | 9 |
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| container_title | The Journal of immunology (1950) |
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| creator | Zhao, Fei Linda Ahn, Jeeyoon Jennifer Chen, Edward L Y Yi, Tae Joon Stickle, Natalie H Spaner, David Zúñiga-Pflücker, Juan Carlos Dunn, Shannon E |
| description | During T cell development, progenitor thymocytes undergo a large proliferative burst immediately following successful TCRβ rearrangement, and defects in genes that regulate this proliferation have a profound effect on thymus cellularity and output. Although the signaling pathways that initiate cell cycling and nutrient uptake after TCRβ selection are understood, less is known about the transcriptional programs that regulate the metabolic machinery to promote biomass accumulation during this process. In this article, we report that mice with whole body deficiency in the nuclear receptor peroxisome proliferator-activated receptor-δ (PPARδ
) exhibit a reduction in spleen and thymus cellularity, with a decrease in thymocyte cell number starting at the double-negative 4 stage of thymocyte development. Although in vivo DNA synthesis was normal in PPARδ
thymocytes, studies in the OP9-delta-like 4 in vitro system of differentiation revealed that PPARδ
double-negative 3 cells underwent fewer cell divisions. Naive CD4
T cells from PPARδ
mice also exhibited reduced proliferation upon TCR and CD28 stimulation in vitro. Growth defects in PPAR-δ-deficient thymocytes and peripheral CD4
T cells correlated with decreases in extracellular acidification rate, mitochondrial reserve, and expression of a host of genes involved in glycolysis, oxidative phosphorylation, and lipogenesis. By contrast, mice with T cell-restricted deficiency of
starting at the double-positive stage of thymocyte development, although exhibiting defective CD4
T cell growth, possessed a normal T cell compartment, pointing to developmental defects as a cause of peripheral T cell lymphopenia in PPARδ
mice. These findings implicate PPAR-δ as a regulator of the metabolic program during thymocyte and T cell growth. |
| doi_str_mv | 10.4049/jimmunol.1800374 |
| format | article |
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) exhibit a reduction in spleen and thymus cellularity, with a decrease in thymocyte cell number starting at the double-negative 4 stage of thymocyte development. Although in vivo DNA synthesis was normal in PPARδ
thymocytes, studies in the OP9-delta-like 4 in vitro system of differentiation revealed that PPARδ
double-negative 3 cells underwent fewer cell divisions. Naive CD4
T cells from PPARδ
mice also exhibited reduced proliferation upon TCR and CD28 stimulation in vitro. Growth defects in PPAR-δ-deficient thymocytes and peripheral CD4
T cells correlated with decreases in extracellular acidification rate, mitochondrial reserve, and expression of a host of genes involved in glycolysis, oxidative phosphorylation, and lipogenesis. By contrast, mice with T cell-restricted deficiency of
starting at the double-positive stage of thymocyte development, although exhibiting defective CD4
T cell growth, possessed a normal T cell compartment, pointing to developmental defects as a cause of peripheral T cell lymphopenia in PPARδ
mice. These findings implicate PPAR-δ as a regulator of the metabolic program during thymocyte and T cell growth.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1800374</identifier><identifier>PMID: 30257885</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - metabolism ; Cell Differentiation - immunology ; Cell Proliferation - physiology ; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor ; Mice ; Mice, Inbred C57BL ; Receptors, Antigen, T-Cell, alpha-beta - immunology ; Receptors, Cytoplasmic and Nuclear - metabolism ; Thymocytes - immunology ; Thymocytes - metabolism</subject><ispartof>The Journal of immunology (1950), 2018-11, Vol.201 (9), p.2664-2682</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-8bb8a1eb6a8e188a645df9caa00dda9cf2400307bad3edda2dc0601d9cc0b5b23</citedby><cites>FETCH-LOGICAL-c341t-8bb8a1eb6a8e188a645df9caa00dda9cf2400307bad3edda2dc0601d9cc0b5b23</cites><orcidid>0000-0002-1431-6351 ; 0000-0001-7197-2243 ; 0000-0003-2538-3178</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30257885$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Fei Linda</creatorcontrib><creatorcontrib>Ahn, Jeeyoon Jennifer</creatorcontrib><creatorcontrib>Chen, Edward L Y</creatorcontrib><creatorcontrib>Yi, Tae Joon</creatorcontrib><creatorcontrib>Stickle, Natalie H</creatorcontrib><creatorcontrib>Spaner, David</creatorcontrib><creatorcontrib>Zúñiga-Pflücker, Juan Carlos</creatorcontrib><creatorcontrib>Dunn, Shannon E</creatorcontrib><title>Peroxisome Proliferator-Activated Receptor-δ Supports the Metabolic Requirements of Cell Growth in TCRβ-Selected Thymocytes and Peripheral CD4 + T Cells</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>During T cell development, progenitor thymocytes undergo a large proliferative burst immediately following successful TCRβ rearrangement, and defects in genes that regulate this proliferation have a profound effect on thymus cellularity and output. Although the signaling pathways that initiate cell cycling and nutrient uptake after TCRβ selection are understood, less is known about the transcriptional programs that regulate the metabolic machinery to promote biomass accumulation during this process. In this article, we report that mice with whole body deficiency in the nuclear receptor peroxisome proliferator-activated receptor-δ (PPARδ
) exhibit a reduction in spleen and thymus cellularity, with a decrease in thymocyte cell number starting at the double-negative 4 stage of thymocyte development. Although in vivo DNA synthesis was normal in PPARδ
thymocytes, studies in the OP9-delta-like 4 in vitro system of differentiation revealed that PPARδ
double-negative 3 cells underwent fewer cell divisions. Naive CD4
T cells from PPARδ
mice also exhibited reduced proliferation upon TCR and CD28 stimulation in vitro. Growth defects in PPAR-δ-deficient thymocytes and peripheral CD4
T cells correlated with decreases in extracellular acidification rate, mitochondrial reserve, and expression of a host of genes involved in glycolysis, oxidative phosphorylation, and lipogenesis. By contrast, mice with T cell-restricted deficiency of
starting at the double-positive stage of thymocyte development, although exhibiting defective CD4
T cell growth, possessed a normal T cell compartment, pointing to developmental defects as a cause of peripheral T cell lymphopenia in PPARδ
mice. These findings implicate PPAR-δ as a regulator of the metabolic program during thymocyte and T cell growth.</description><subject>Animals</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>Cell Differentiation - immunology</subject><subject>Cell Proliferation - physiology</subject><subject>Gene Rearrangement, beta-Chain T-Cell Antigen Receptor</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Receptors, Antigen, T-Cell, alpha-beta - immunology</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Thymocytes - immunology</subject><subject>Thymocytes - metabolism</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNo9UdtKJDEQDeKis7O--yR5FJbWSvo6j9KuF1B2GMfnJp1UM5HuTpuk1fkVP0P2O_wmMzouFBRUnXPqUIeQQwYnCSSz0wfddWNv2hNWAMR5skMmLE0hyjLIdskEgPOI5Vm-T3469wAAGfBkj-zHwNO8KNIJeZ2jNS_amQ7p3JpWN2iFNzY6k14_CY-KLlDisBm9_6N34zAY6x31K6S36EUdKDJAHkdtscM-rExDS2xbemnNs19R3dNluXh_i-6wRbkRXK7WnZFrj46KXtHgQA-rcLal5XlCf9PlJ9_9Ij8a0To82PYpub_4syyvopu_l9fl2U0k44T5qKjrQjCsM1EgKwqRJalqZlIIAKXETDY8Cb-BvBYqxjDhSoY3MDWTEuq05vGUHH_pDtY8juh81WkngwPRoxldxRmLeZbHoaYEvqDSGucsNtVgdSfsumJQbRKpvhOptokEytFWfaw7VP8J3xHEH6k5jbA</recordid><startdate>20181101</startdate><enddate>20181101</enddate><creator>Zhao, Fei Linda</creator><creator>Ahn, Jeeyoon Jennifer</creator><creator>Chen, Edward L Y</creator><creator>Yi, Tae Joon</creator><creator>Stickle, Natalie H</creator><creator>Spaner, David</creator><creator>Zúñiga-Pflücker, Juan Carlos</creator><creator>Dunn, Shannon E</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/0000-0002-1431-6351</orcidid><orcidid>https://orcid.org/0000-0001-7197-2243</orcidid><orcidid>https://orcid.org/0000-0003-2538-3178</orcidid></search><sort><creationdate>20181101</creationdate><title>Peroxisome Proliferator-Activated Receptor-δ Supports the Metabolic Requirements of Cell Growth in TCRβ-Selected Thymocytes and Peripheral CD4 + T Cells</title><author>Zhao, Fei Linda ; Ahn, Jeeyoon Jennifer ; Chen, Edward L Y ; Yi, Tae Joon ; Stickle, Natalie H ; Spaner, David ; Zúñiga-Pflücker, Juan Carlos ; Dunn, Shannon E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c341t-8bb8a1eb6a8e188a645df9caa00dda9cf2400307bad3edda2dc0601d9cc0b5b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>Cell Differentiation - immunology</topic><topic>Cell Proliferation - physiology</topic><topic>Gene Rearrangement, beta-Chain T-Cell Antigen Receptor</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Receptors, Antigen, T-Cell, alpha-beta - immunology</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Thymocytes - immunology</topic><topic>Thymocytes - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Fei Linda</creatorcontrib><creatorcontrib>Ahn, Jeeyoon Jennifer</creatorcontrib><creatorcontrib>Chen, Edward L Y</creatorcontrib><creatorcontrib>Yi, Tae Joon</creatorcontrib><creatorcontrib>Stickle, Natalie H</creatorcontrib><creatorcontrib>Spaner, David</creatorcontrib><creatorcontrib>Zúñiga-Pflücker, Juan Carlos</creatorcontrib><creatorcontrib>Dunn, Shannon E</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>Zhao, Fei Linda</au><au>Ahn, Jeeyoon Jennifer</au><au>Chen, Edward L Y</au><au>Yi, Tae Joon</au><au>Stickle, Natalie H</au><au>Spaner, David</au><au>Zúñiga-Pflücker, Juan Carlos</au><au>Dunn, Shannon E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Peroxisome Proliferator-Activated Receptor-δ Supports the Metabolic Requirements of Cell Growth in TCRβ-Selected Thymocytes and Peripheral CD4 + T Cells</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2018-11-01</date><risdate>2018</risdate><volume>201</volume><issue>9</issue><spage>2664</spage><epage>2682</epage><pages>2664-2682</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>During T cell development, progenitor thymocytes undergo a large proliferative burst immediately following successful TCRβ rearrangement, and defects in genes that regulate this proliferation have a profound effect on thymus cellularity and output. Although the signaling pathways that initiate cell cycling and nutrient uptake after TCRβ selection are understood, less is known about the transcriptional programs that regulate the metabolic machinery to promote biomass accumulation during this process. In this article, we report that mice with whole body deficiency in the nuclear receptor peroxisome proliferator-activated receptor-δ (PPARδ
) exhibit a reduction in spleen and thymus cellularity, with a decrease in thymocyte cell number starting at the double-negative 4 stage of thymocyte development. Although in vivo DNA synthesis was normal in PPARδ
thymocytes, studies in the OP9-delta-like 4 in vitro system of differentiation revealed that PPARδ
double-negative 3 cells underwent fewer cell divisions. Naive CD4
T cells from PPARδ
mice also exhibited reduced proliferation upon TCR and CD28 stimulation in vitro. Growth defects in PPAR-δ-deficient thymocytes and peripheral CD4
T cells correlated with decreases in extracellular acidification rate, mitochondrial reserve, and expression of a host of genes involved in glycolysis, oxidative phosphorylation, and lipogenesis. By contrast, mice with T cell-restricted deficiency of
starting at the double-positive stage of thymocyte development, although exhibiting defective CD4
T cell growth, possessed a normal T cell compartment, pointing to developmental defects as a cause of peripheral T cell lymphopenia in PPARδ
mice. These findings implicate PPAR-δ as a regulator of the metabolic program during thymocyte and T cell growth.</abstract><cop>United States</cop><pmid>30257885</pmid><doi>10.4049/jimmunol.1800374</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0002-1431-6351</orcidid><orcidid>https://orcid.org/0000-0001-7197-2243</orcidid><orcidid>https://orcid.org/0000-0003-2538-3178</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of immunology (1950), 2018-11, Vol.201 (9), p.2664-2682 |
| issn | 0022-1767 1550-6606 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2113267367 |
| source | Free E-Journal (出版社公開部分のみ） |
| subjects | Animals CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - metabolism Cell Differentiation - immunology Cell Proliferation - physiology Gene Rearrangement, beta-Chain T-Cell Antigen Receptor Mice Mice, Inbred C57BL Receptors, Antigen, T-Cell, alpha-beta - immunology Receptors, Cytoplasmic and Nuclear - metabolism Thymocytes - immunology Thymocytes - metabolism |
| title | Peroxisome Proliferator-Activated Receptor-δ Supports the Metabolic Requirements of Cell Growth in TCRβ-Selected Thymocytes and Peripheral CD4 + T Cells |
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