A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ TREG differentiation
The Tec kinases ITK (interleukin-2-inducible T-cell kinase) and RLK (resting lymphocyte kinase) are critical components of the proximal TCR/CD3 signal transduction machinery, and data in mice suggest that ITK negatively modulates regulatory T cell (TREG) differentiation. However, whether Tec kinases...
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| creator | Mamontov, Polina Eberwine, Ryan A Perrigoue, Jackie Das, Anuk Friedman, Joshua R Mora, J Rodrigo |
| description | The Tec kinases ITK (interleukin-2-inducible T-cell kinase) and RLK (resting lymphocyte kinase) are critical components of the proximal TCR/CD3 signal transduction machinery, and data in mice suggest that ITK negatively modulates regulatory T cell (TREG) differentiation. However, whether Tec kinases modulate TREG development and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), we found that ITK knockdown in human primary naïve peripheral blood CD4 T cells increased Foxp3+ expression under both TREG and T helper priming conditions. TREG differentiated under ITK knockdown conditions exhibited enhanced expression of the co-inhibitory receptor PD-1 and were suppressive in a T cell proliferation assay. ITK knockdown decreased IL-17A production in T cells primed under Th17 conditions and promoted Th1 differentiation. Lastly, a dual ITK/RLK Tec kinase inhibitor did not induce Foxp3 in CD4 T cells, but conversely abrogated Foxp3 expression induced by ITK knockdown. Our data suggest that targeting ITK in human T cells may be an effective approach to boost TREG in the context of autoimmune diseases, but concomitant inhibition of other Tec family kinases may negate this effect. |
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However, whether Tec kinases modulate TREG development and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), we found that ITK knockdown in human primary naïve peripheral blood CD4 T cells increased Foxp3+ expression under both TREG and T helper priming conditions. TREG differentiated under ITK knockdown conditions exhibited enhanced expression of the co-inhibitory receptor PD-1 and were suppressive in a T cell proliferation assay. ITK knockdown decreased IL-17A production in T cells primed under Th17 conditions and promoted Th1 differentiation. Lastly, a dual ITK/RLK Tec kinase inhibitor did not induce Foxp3 in CD4 T cells, but conversely abrogated Foxp3 expression induced by ITK knockdown. Our data suggest that targeting ITK in human T cells may be an effective approach to boost TREG in the context of autoimmune diseases, but concomitant inhibition of other Tec family kinases may negate this effect.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0215963</identifier><identifier>PMID: 31022269</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Asthma ; Autoimmune diseases ; CD3 antigen ; CD4 antigen ; Cell Differentiation ; Cell Polarity ; Cell proliferation ; Critical components ; Cytokines ; Differentiation ; Disease ; Enzyme inhibitors ; Forkhead Transcription Factors - metabolism ; Foxp3 protein ; Gene expression ; Helper cells ; Humans ; Immune system ; Interleukin 2 ; Itk protein ; Kinases ; Lymphocyte Activation - immunology ; Lymphocytes ; Lymphocytes T ; PD-1 protein ; Peripheral blood ; Priming ; Programmed Cell Death 1 Receptor - metabolism ; Protein Kinase Inhibitors - pharmacology ; Protein-Tyrosine Kinases - metabolism ; R&D ; Research & development ; siRNA ; T cell receptors ; T-cell receptor ; T-Lymphocytes, Regulatory - cytology ; T-Lymphocytes, Regulatory - enzymology ; Th1 Cells - cytology ; Th17 Cells - cytology ; Up-Regulation - drug effects</subject><ispartof>PloS one, 2019, Vol.14 (4), p.e0215963-e0215963</ispartof><rights>2019 Mamontov et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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However, whether Tec kinases modulate TREG development and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), we found that ITK knockdown in human primary naïve peripheral blood CD4 T cells increased Foxp3+ expression under both TREG and T helper priming conditions. TREG differentiated under ITK knockdown conditions exhibited enhanced expression of the co-inhibitory receptor PD-1 and were suppressive in a T cell proliferation assay. ITK knockdown decreased IL-17A production in T cells primed under Th17 conditions and promoted Th1 differentiation. Lastly, a dual ITK/RLK Tec kinase inhibitor did not induce Foxp3 in CD4 T cells, but conversely abrogated Foxp3 expression induced by ITK knockdown. Our data suggest that targeting ITK in human T cells may be an effective approach to boost TREG in the context of autoimmune diseases, but concomitant inhibition of other Tec family kinases may negate this effect.</description><subject>Asthma</subject><subject>Autoimmune diseases</subject><subject>CD3 antigen</subject><subject>CD4 antigen</subject><subject>Cell Differentiation</subject><subject>Cell Polarity</subject><subject>Cell proliferation</subject><subject>Critical components</subject><subject>Cytokines</subject><subject>Differentiation</subject><subject>Disease</subject><subject>Enzyme inhibitors</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Foxp3 protein</subject><subject>Gene expression</subject><subject>Helper cells</subject><subject>Humans</subject><subject>Immune system</subject><subject>Interleukin 2</subject><subject>Itk protein</subject><subject>Kinases</subject><subject>Lymphocyte Activation - immunology</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>PD-1 protein</subject><subject>Peripheral blood</subject><subject>Priming</subject><subject>Programmed Cell Death 1 Receptor - 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metabolism</topic><topic>Foxp3 protein</topic><topic>Gene expression</topic><topic>Helper cells</topic><topic>Humans</topic><topic>Immune system</topic><topic>Interleukin 2</topic><topic>Itk protein</topic><topic>Kinases</topic><topic>Lymphocyte Activation - immunology</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>PD-1 protein</topic><topic>Peripheral blood</topic><topic>Priming</topic><topic>Programmed Cell Death 1 Receptor - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>R&D</topic><topic>Research & development</topic><topic>siRNA</topic><topic>T cell receptors</topic><topic>T-cell receptor</topic><topic>T-Lymphocytes, Regulatory - cytology</topic><topic>T-Lymphocytes, Regulatory - enzymology</topic><topic>Th1 Cells - cytology</topic><topic>Th17 Cells - cytology</topic><topic>Up-Regulation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mamontov, Polina</creatorcontrib><creatorcontrib>Eberwine, Ryan A</creatorcontrib><creatorcontrib>Perrigoue, Jackie</creatorcontrib><creatorcontrib>Das, Anuk</creatorcontrib><creatorcontrib>Friedman, Joshua R</creatorcontrib><creatorcontrib>Mora, J Rodrigo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</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>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mamontov, Polina</au><au>Eberwine, Ryan A</au><au>Perrigoue, Jackie</au><au>Das, Anuk</au><au>Friedman, Joshua R</au><au>Mora, J Rodrigo</au><au>Piccirillo, Ciriaco A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ TREG differentiation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019</date><risdate>2019</risdate><volume>14</volume><issue>4</issue><spage>e0215963</spage><epage>e0215963</epage><pages>e0215963-e0215963</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The Tec kinases ITK (interleukin-2-inducible T-cell kinase) and RLK (resting lymphocyte kinase) are critical components of the proximal TCR/CD3 signal transduction machinery, and data in mice suggest that ITK negatively modulates regulatory T cell (TREG) differentiation. However, whether Tec kinases modulate TREG development and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), we found that ITK knockdown in human primary naïve peripheral blood CD4 T cells increased Foxp3+ expression under both TREG and T helper priming conditions. TREG differentiated under ITK knockdown conditions exhibited enhanced expression of the co-inhibitory receptor PD-1 and were suppressive in a T cell proliferation assay. ITK knockdown decreased IL-17A production in T cells primed under Th17 conditions and promoted Th1 differentiation. Lastly, a dual ITK/RLK Tec kinase inhibitor did not induce Foxp3 in CD4 T cells, but conversely abrogated Foxp3 expression induced by ITK knockdown. Our data suggest that targeting ITK in human T cells may be an effective approach to boost TREG in the context of autoimmune diseases, but concomitant inhibition of other Tec family kinases may negate this effect.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31022269</pmid><doi>10.1371/journal.pone.0215963</doi><orcidid>https://orcid.org/0000-0001-8819-0950</orcidid><orcidid>https://orcid.org/0000-0001-9382-8429</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Asthma Autoimmune diseases CD3 antigen CD4 antigen Cell Differentiation Cell Polarity Cell proliferation Critical components Cytokines Differentiation Disease Enzyme inhibitors Forkhead Transcription Factors - metabolism Foxp3 protein Gene expression Helper cells Humans Immune system Interleukin 2 Itk protein Kinases Lymphocyte Activation - immunology Lymphocytes Lymphocytes T PD-1 protein Peripheral blood Priming Programmed Cell Death 1 Receptor - metabolism Protein Kinase Inhibitors - pharmacology Protein-Tyrosine Kinases - metabolism R&D Research & development siRNA T cell receptors T-cell receptor T-Lymphocytes, Regulatory - cytology T-Lymphocytes, Regulatory - enzymology Th1 Cells - cytology Th17 Cells - cytology Up-Regulation - drug effects |
| title | A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ TREG differentiation |
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