EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia
The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4 + T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4 + T cells in lymph nodes (LNs) of pat...
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| Veröffentlicht in: | Leukemia 2021-08, Vol.35 (8), p.2311-2324 |
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| creator | Roessner, Philipp M. Llaó Cid, Laura Lupar, Ekaterina Roider, Tobias Bordas, Marie Schifflers, Christoph Arseni, Lavinia Gaupel, Ann-Christin Kilpert, Fabian Krötschel, Marit Arnold, Sebastian J. Sellner, Leopold Colomer, Dolors Stilgenbauer, Stephan Dietrich, Sascha Lichter, Peter Izcue, Ana Seiffert, Martina |
| description | The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4
+
T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4
+
T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4
+
T cells, that is enriched in genes typical for T regulatory type 1 (T
R
1) cells. The T
R
1 cell identity of these CD4
+
T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. T
R
1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4
+
T cells control TCL1 leukemia development after adoptive transfer in leukopenic
Rag2
−/
−
mice, EOMES-deficient CD4
+
T cells failed to do so. We further show that T
R
1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as
Il10rb
-deficient CD4
+
T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic T
R
1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner. |
| doi_str_mv | 10.1038/s41375-021-01136-1 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8324479</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2556540792</sourcerecordid><originalsourceid>FETCH-LOGICAL-c474t-61c3f32863d7a8399b5f6a6705a170103e4d9d724804299bcdb323d9d7aeb2583</originalsourceid><addsrcrecordid>eNp9kUtvEzEUhS1ERdPCH2CBLLFEBr_t2SChEEqloC4oa8vxeBKXmXGwPZXm3-M0fbFhZet-5557rw4Abwn-SDDTnzInTAmEKUGYECYReQEWhCuJhBDkJVhgrRWSDeWn4CznG4wPUL4Cp4wJKrUkCxBXVz9WP6EdW3i5RgTD5LdTb4uvpRLKNMQErSvhNpQZxg5ePwhimmGZ9x4SuPzKP1TgfN9nGEbodimOwcF-Hva76OZy-Pvptx-CfQ1OOttn_-b-PQe_vq2ul9_R-uricvlljRxXvCBJHOsY1ZK1ymrWNBvRSSsVFpYoXK_3vG1aRbnGnFbq2g2j7FCyfkOFZufg89F3P20G3zo_lmR7s09hsGk20QbzLxnDzmzjrdGMcq6aavD-3iDFP5PPxdzEKY11Z0OFkIJj1dCqokeVSzHn5LvHCQSbQ0jmGJKpIZm7kAypTe-e7_bY8pBKFbCjIFc0bn16mv0f27-tKpxH</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2556540792</pqid></control><display><type>article</type><title>EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Roessner, Philipp M. ; Llaó Cid, Laura ; Lupar, Ekaterina ; Roider, Tobias ; Bordas, Marie ; Schifflers, Christoph ; Arseni, Lavinia ; Gaupel, Ann-Christin ; Kilpert, Fabian ; Krötschel, Marit ; Arnold, Sebastian J. ; Sellner, Leopold ; Colomer, Dolors ; Stilgenbauer, Stephan ; Dietrich, Sascha ; Lichter, Peter ; Izcue, Ana ; Seiffert, Martina</creator><creatorcontrib>Roessner, Philipp M. ; Llaó Cid, Laura ; Lupar, Ekaterina ; Roider, Tobias ; Bordas, Marie ; Schifflers, Christoph ; Arseni, Lavinia ; Gaupel, Ann-Christin ; Kilpert, Fabian ; Krötschel, Marit ; Arnold, Sebastian J. ; Sellner, Leopold ; Colomer, Dolors ; Stilgenbauer, Stephan ; Dietrich, Sascha ; Lichter, Peter ; Izcue, Ana ; Seiffert, Martina</creatorcontrib><description>The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4
+
T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4
+
T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4
+
T cells, that is enriched in genes typical for T regulatory type 1 (T
R
1) cells. The T
R
1 cell identity of these CD4
+
T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. T
R
1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4
+
T cells control TCL1 leukemia development after adoptive transfer in leukopenic
Rag2
−/
−
mice, EOMES-deficient CD4
+
T cells failed to do so. We further show that T
R
1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as
Il10rb
-deficient CD4
+
T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic T
R
1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-021-01136-1</identifier><identifier>PMID: 33526861</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/31 ; 42/35 ; 631/250/1619/554/1898 ; 631/250/580/1884 ; 631/67/1990/283/1895 ; 631/67/1990/291/1621 ; 631/67/327 ; 64/110 ; 96/21 ; Adoptive transfer ; Animals ; Anticancer properties ; Antitumor activity ; Apoptosis ; B-cell lymphoma ; Cancer Research ; CD4 antigen ; CD4-Positive T-Lymphocytes - immunology ; Cell death ; Cell Differentiation ; Chronic lymphocytic leukemia ; Critical Care Medicine ; Cytotoxicity ; Female ; Flow cytometry ; Gene Expression Regulation, Leukemic ; Hematology ; Humans ; Intensive ; Interferon ; Interferon-gamma ; Interleukin 1 ; Interleukin 10 ; Interleukin-10 - genetics ; Interleukin-10 - metabolism ; Internal Medicine ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - immunology ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell - pathology ; Leukemia, Lymphocytic, Chronic, B-Cell - prevention & control ; Lymph nodes ; Lymphatic leukemia ; Lymphocytes ; Lymphocytes B ; Lymphocytes T ; Lymphoma ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred C57BL ; Oncology ; PD-1 protein ; Prognosis ; RAG2 protein ; Receptors ; Signal Transduction ; T-Box Domain Proteins - genetics ; T-Box Domain Proteins - metabolism ; T-Lymphocytes, Cytotoxic - immunology ; T-Lymphocytes, Regulatory - immunology ; Th1 Cells - immunology ; Transcriptome ; Transcriptomes ; Tumor Cells, Cultured</subject><ispartof>Leukemia, 2021-08, Vol.35 (8), p.2311-2324</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-61c3f32863d7a8399b5f6a6705a170103e4d9d724804299bcdb323d9d7aeb2583</citedby><cites>FETCH-LOGICAL-c474t-61c3f32863d7a8399b5f6a6705a170103e4d9d724804299bcdb323d9d7aeb2583</cites><orcidid>0000-0001-7486-8484 ; 0000-0001-5155-663X ; 0000-0002-2960-5279 ; 0000-0001-7061-5690 ; 0000-0002-6973-3531 ; 0000-0002-7974-7451 ; 0000-0002-2688-9210 ; 0000-0002-2266-8621 ; 0000-0002-7893-401X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33526861$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Roessner, Philipp M.</creatorcontrib><creatorcontrib>Llaó Cid, Laura</creatorcontrib><creatorcontrib>Lupar, Ekaterina</creatorcontrib><creatorcontrib>Roider, Tobias</creatorcontrib><creatorcontrib>Bordas, Marie</creatorcontrib><creatorcontrib>Schifflers, Christoph</creatorcontrib><creatorcontrib>Arseni, Lavinia</creatorcontrib><creatorcontrib>Gaupel, Ann-Christin</creatorcontrib><creatorcontrib>Kilpert, Fabian</creatorcontrib><creatorcontrib>Krötschel, Marit</creatorcontrib><creatorcontrib>Arnold, Sebastian J.</creatorcontrib><creatorcontrib>Sellner, Leopold</creatorcontrib><creatorcontrib>Colomer, Dolors</creatorcontrib><creatorcontrib>Stilgenbauer, Stephan</creatorcontrib><creatorcontrib>Dietrich, Sascha</creatorcontrib><creatorcontrib>Lichter, Peter</creatorcontrib><creatorcontrib>Izcue, Ana</creatorcontrib><creatorcontrib>Seiffert, Martina</creatorcontrib><title>EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4
+
T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4
+
T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4
+
T cells, that is enriched in genes typical for T regulatory type 1 (T
R
1) cells. The T
R
1 cell identity of these CD4
+
T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. T
R
1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4
+
T cells control TCL1 leukemia development after adoptive transfer in leukopenic
Rag2
−/
−
mice, EOMES-deficient CD4
+
T cells failed to do so. We further show that T
R
1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as
Il10rb
-deficient CD4
+
T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic T
R
1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.</description><subject>13/31</subject><subject>42/35</subject><subject>631/250/1619/554/1898</subject><subject>631/250/580/1884</subject><subject>631/67/1990/283/1895</subject><subject>631/67/1990/291/1621</subject><subject>631/67/327</subject><subject>64/110</subject><subject>96/21</subject><subject>Adoptive transfer</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>B-cell lymphoma</subject><subject>Cancer Research</subject><subject>CD4 antigen</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>Cell death</subject><subject>Cell Differentiation</subject><subject>Chronic lymphocytic leukemia</subject><subject>Critical Care Medicine</subject><subject>Cytotoxicity</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Hematology</subject><subject>Humans</subject><subject>Intensive</subject><subject>Interferon</subject><subject>Interferon-gamma</subject><subject>Interleukin 1</subject><subject>Interleukin 10</subject><subject>Interleukin-10 - genetics</subject><subject>Interleukin-10 - metabolism</subject><subject>Internal Medicine</subject><subject>Leukemia</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - immunology</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - prevention & control</subject><subject>Lymph nodes</subject><subject>Lymphatic leukemia</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Lymphocytes T</subject><subject>Lymphoma</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Oncology</subject><subject>PD-1 protein</subject><subject>Prognosis</subject><subject>RAG2 protein</subject><subject>Receptors</subject><subject>Signal Transduction</subject><subject>T-Box Domain Proteins - genetics</subject><subject>T-Box Domain Proteins - metabolism</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Th1 Cells - immunology</subject><subject>Transcriptome</subject><subject>Transcriptomes</subject><subject>Tumor Cells, 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Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Roessner, Philipp M.</au><au>Llaó Cid, Laura</au><au>Lupar, Ekaterina</au><au>Roider, Tobias</au><au>Bordas, Marie</au><au>Schifflers, Christoph</au><au>Arseni, Lavinia</au><au>Gaupel, Ann-Christin</au><au>Kilpert, Fabian</au><au>Krötschel, Marit</au><au>Arnold, Sebastian J.</au><au>Sellner, Leopold</au><au>Colomer, Dolors</au><au>Stilgenbauer, Stephan</au><au>Dietrich, Sascha</au><au>Lichter, Peter</au><au>Izcue, Ana</au><au>Seiffert, Martina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2021-08-01</date><risdate>2021</risdate><volume>35</volume><issue>8</issue><spage>2311</spage><epage>2324</epage><pages>2311-2324</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4
+
T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4
+
T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4
+
T cells, that is enriched in genes typical for T regulatory type 1 (T
R
1) cells. The T
R
1 cell identity of these CD4
+
T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. T
R
1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4
+
T cells control TCL1 leukemia development after adoptive transfer in leukopenic
Rag2
−/
−
mice, EOMES-deficient CD4
+
T cells failed to do so. We further show that T
R
1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as
Il10rb
-deficient CD4
+
T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic T
R
1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33526861</pmid><doi>10.1038/s41375-021-01136-1</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-7486-8484</orcidid><orcidid>https://orcid.org/0000-0001-5155-663X</orcidid><orcidid>https://orcid.org/0000-0002-2960-5279</orcidid><orcidid>https://orcid.org/0000-0001-7061-5690</orcidid><orcidid>https://orcid.org/0000-0002-6973-3531</orcidid><orcidid>https://orcid.org/0000-0002-7974-7451</orcidid><orcidid>https://orcid.org/0000-0002-2688-9210</orcidid><orcidid>https://orcid.org/0000-0002-2266-8621</orcidid><orcidid>https://orcid.org/0000-0002-7893-401X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2021-08, Vol.35 (8), p.2311-2324 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8324479 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | 13/31 42/35 631/250/1619/554/1898 631/250/580/1884 631/67/1990/283/1895 631/67/1990/291/1621 631/67/327 64/110 96/21 Adoptive transfer Animals Anticancer properties Antitumor activity Apoptosis B-cell lymphoma Cancer Research CD4 antigen CD4-Positive T-Lymphocytes - immunology Cell death Cell Differentiation Chronic lymphocytic leukemia Critical Care Medicine Cytotoxicity Female Flow cytometry Gene Expression Regulation, Leukemic Hematology Humans Intensive Interferon Interferon-gamma Interleukin 1 Interleukin 10 Interleukin-10 - genetics Interleukin-10 - metabolism Internal Medicine Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - immunology Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Leukemia, Lymphocytic, Chronic, B-Cell - pathology Leukemia, Lymphocytic, Chronic, B-Cell - prevention & control Lymph nodes Lymphatic leukemia Lymphocytes Lymphocytes B Lymphocytes T Lymphoma Medicine Medicine & Public Health Mice Mice, Inbred C57BL Oncology PD-1 protein Prognosis RAG2 protein Receptors Signal Transduction T-Box Domain Proteins - genetics T-Box Domain Proteins - metabolism T-Lymphocytes, Cytotoxic - immunology T-Lymphocytes, Regulatory - immunology Th1 Cells - immunology Transcriptome Transcriptomes Tumor Cells, Cultured |
| title | EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia |
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