{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T02:59:53Z","timestamp":1787972393924,"version":"build-2784847793"},"reference-count":81,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T00:00:00Z","timestamp":1699488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"VoLo Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The role of natural killer group 2D (NKG2D) in peripheral T cells as a costimulatory receptor is well established. However, its contribution to T cell thymic education and functional imprint is unknown. Here, we report significant changes in development, receptor signaling, transcriptional program, and function in T cells from mice lacking NKG2D signaling. In C57BL\/6 (B6) and OT-I mice, we found that NKG2D deficiency results in V\u03b2 chain usage changes and stagnation of the double-positive stage in thymic T cell development. We found that the expression of CD5 and CD45 in thymocytes from NKG2D deficient mice were reduced, indicating a direct influence of NKG2D on the strength of T cell receptor (TCR) signaling during the developmental stage of T cells. Depicting the functional consequences of NKG2D, peripheral OT-I NKG2D-deficient cells were unresponsive to ovalbumin peptide stimulation. Paradoxically, while \u03b1CD3\/CD28 agonist antibodies led to phenotypic T cell activation, their ability to produce cytokines remained severely compromised. We found that OT-I NKG2D-deficient cells activate STAT5 in response to interleukin-15 but were unable to phosphorylate ERK or S6 upon TCR engagement, underpinning a defect in TCR signaling. Finally, we showed that NKG2D is expressed in mouse and human thymic T cells at the double-negative stage, suggesting an evolutionarily conserved function during T cell development. The data presented in this study indicate that NKG2D impacts thymic T cell development at a fundamental level by reducing the TCR threshold and affecting the functional imprint of the thymic progeny. In summary, understanding the impact of NKG2D on thymic T cell development and TCR signaling contributes to our knowledge of immune system regulation, immune dysregulation, and the design of immunotherapies.<\/jats:p>","DOI":"10.1093\/jleuko\/qiad130","type":"journal-article","created":{"date-parts":[[2023,11,11]],"date-time":"2023-11-11T03:11:47Z","timestamp":1699672307000},"page":"306-321","source":"Crossref","is-referenced-by-count":5,"title":["NKG2D receptor signaling shapes T cell thymic education"],"prefix":"10.1093","volume":"115","author":[{"given":"Cynthia","family":"Perez","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lourdes","family":"Plaza-Rojas","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, FL 33612, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin C","family":"Boucher","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, FL 33612, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mate Z","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, FL 33612, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Kostenko","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, FL 33612, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kushal","family":"Prajapati","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna","family":"Burke","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Delos","family":"Reyes","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L","family":"Austin","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, FL 33612, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States"},{"name":"Department of Microbiology and Immunology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phong T","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States"},{"name":"Department of Microbiology and Immunology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 A","family":"Guevara-Patino","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Loyola University Chicago , 2160 S. First Ave, Maywood, IL 60153 , United States"},{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, FL 33612, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,11,9]]},"reference":[{"issue":"4","key":"2024012011551588900_qiad130-B1","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/j.1460-2075.1991.tb08024.x","article-title":"Development of the CD4 and CD8 lineage of T cells: instruction versus selection","volume":"10","author":"Borgulya","year":"1991","journal-title":"EMBO J"},{"issue":"6","key":"2024012011551588900_qiad130-B2","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.it.2012.03.005","article-title":"Thymic epithelial cells: working class heroes for T cell development and repertoire selection","volume":"33","author":"Anderson","year":"2012","journal-title":"Trends 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