@article{e46eb41bce1043e296b8d3fb716cce95,
title = "Identification of lineage-specifying cytokines that signal all CD8 + -cytotoxic-lineage-fate 'decisions' in the thymus",
abstract = "T cell antigen receptor (TCR) signaling in the thymus initiates positive selection, but the CD8 + -lineage fate is thought to be induced by cytokines after TCR signaling has ceased, although this remains controversial and unproven. We have identified four cytokines (IL-6, IFN-3, TSLP and TGF-β) that did not signal via the common 3-chain (3 c) receptor but that, like IL-7 and IL-15, induced expression of the lineage-specifying transcription factor Runx3d and signaled the generation of CD8 + T cells. Elimination of in vivo signaling by all six of these 'lineage-specifying cytokines' during positive selection eliminated Runx3d expression and completely abolished the generation of CD8 + single-positive thymocytes. Thus, this study proves that signaling during positive selection by lineage-specifying cytokines is responsible for all CD8 + -lineage-fate 'decisions' in the thymus.",
author = "Ruth Etzensperger and Tejas Kadakia and Xuguang Tai and Amala Alag and Guinter, {Terry I.} and Takeshi Egawa and Batu Erman and Alfred Singer",
note = "Funding Information: Animals. Mice with loxP-flanked alleles encoding γc18 were bred to E8III-Cre mice to obtain γccKO mice as previously described18. SOCS1Tg mice20 were provided by M. Kubo; Tslpr−/− (TSLPRKO) mice51 were provided by W. Leonard; Tgfbr1fl/fl mice52 were provided by W. Chen; Runx3dYFP/YFP mice53 were provided by D. Littman; and Zbtb7b−/− (ThPOKKO) mice34 were provided by R. Bosselut. Tgfbr1fl/fl mice were bred to E8III-Cre mice to obtain TGF-βR1cKO mice, while Cbfbfl/fl and Runx1fl/fl mice (from The Jackson Laboratory) were bred to CD4-Cre mice to obtain CBFβcKO and Runx1cKO mice. Il6−/− (IL-6KO), Ifngr1−/− (IFN-γRKO), Il4r−/− (IL-4RαKO), β2mKO, HY RagKO, OT-I RagKO and H2-Ab−/−Cd1d−/− (MHCIIKOCD1dKO) mice were bred in our own animal colony at the National Cancer Institute. C57BL/6 (B6) mice were obtained from the Frederick National Laboratory for Cancer Research. All animal experiments were approved by the National Cancer Institute Animal Care and Use Committee, and mice were cared for in accordance with National Institutes of Health guidelines. Funding Information: We thank T. McCaughtry for initial contributions to the project; J.-H. Park, V. Lazarevic, D. Singer, X. Zhou and M. Kimura for critical reading of the manuscript; M. Kubo (Tokyo University of Science) for SOCSTg mice; W. Leonard (National Heart, Lung and Blood Institute) for TSLPRKO mice; W. Chen (National Institute of Dental and Craniofacial Research) for Tgfbr1fl mice; D. Littman (New York University) for Runx3dYFP mice; R. Bosselut (National Cancer Institute) for ThPOKKO mice; and S. Sharrow, A. Adams and L. Granger for flow cytometry. Supported by the Intramural Research Program of the US National Institutes of Health, the National Cancer Institute, the Center for Cancer Research and the US National Institutes of Health (R01AI097244-01A1 to T.E.). Funding Information: 1Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. 3Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey. Correspondence should be addressed to A.S. (singera@nih.gov). Publisher Copyright: {\textcopyright} 2017 Nature America, Inc., part of Springer Nature. All rights reserved.",
year = "2017",
month = oct,
day = "18",
doi = "10.1038/ni.3847",
language = "English",
volume = "18",
pages = "1218--1227",
journal = "Nature Immunology",
issn = "1529-2908",
number = "11",
}