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Qiao Y , Zhu LQ , Sofi H , Lapinski PE , Horai R , Mueller K , Stritesky GL , He X , Teh HS , Wiest DL , Kappes DJ , King PD , Hogquist KA , Schwartzberg PL , Sant'Angelo DB , Chang CH
Development of promyelocytic leukemia zinc finger-expressing innate CD4 T cells requires stronger T-cell receptor signals than conventional CD4 T cells
Proceedings of the National Academy of Sciences of the United States of America. 2012 Oct;109(40) :16264-16269
PMID: WOS:000309611400065    PMCID: PMC3479572   
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MHC class II-expressing thymocytes and thymic epithelial cells can mediate CD4 T-cell selection resulting in functionally distinct thymocyte-selected CD4 (T-CD4) and epithelial-selected CD4 (E-CD4) T cells, respectively. However, little is known about how T-cell receptor (TCR) signaling influences the development of these two CD4 T-cell subsets. To study TCR signaling for T-CD4 T-cell development, we used a GFP reporter system of Nur77 in which GFP intensity directly correlates with TCR signaling strength. T-CD4 T cells expressed higher levels of GFP than E-CD4 T cells, suggesting that T-CD4 T cells received stronger TCR signaling than E-CD4 T cells during selection. Elimination of Ras GTPase-activating protein enhanced E-CD4 but decreased T-CD4 T-cell selection efficiency, suggesting a shift to negative selection. Conversely, the absence of IL-2-inducible T-cell kinase that causes poor E-CD4 T-cell selection due to insufficient TCR signaling improved T-CD4 T-cell generation, consistent with rescue from negative selection. Strong TCR signaling during T-CD4 T-cell development correlates with the expression of the transcription factor promyelocytic leukemia zinc finger protein. However, although modulation of the signaling strength affected the efficiency of T-CD4 T-cell development during positive and negative selection, the signaling strength is not as important for the effector function of T-CD4 T cells. These findings indicate that innate T-CD4 T cells, together with invariant natural killer T cells and gamma delta T cells, receive strong TCR signals during their development and that signaling requirements for the development and the effector functions are distinct.
Qiao, Yu Zhu, Lingqiao Sofi, Hanief Lapinski, Philip E. Horai, Reiko Mueller, Kristen Stritesky, Gretta L. He, Xi Teh, Hung-Sia Wiest, David L. Kappes, Dietmar J. King, Philip D. Hogquist, Kristin A. Schwartzberg, Pamela L. Sant'Angelo, Derek B. Chang, Cheong-Hee National Institutes of Health (NIH) Grants [T32 CA009138, CA153260, HL096498, AI083988, AI059739]; Robert Wood Johnson Foundation Grant [67038, AI073677]; National Human Genome Research Institute We thank Dr. Terry Geiger for critical reading of the manuscript. This research was supported in part by National Institutes of Health (NIH) Grants T32 CA009138 (to G.L.S.), CA153260 (to D.J.K.); HL096498 (to P.D.K); AI083988 and AI059739 and Robert Wood Johnson Foundation Grant 67038 to the Child Health Institute (to D.B.S.); AI073677 (to C.-H.C.); and by intramural funds from the National Human Genome Research Institute (to P.L.S.). CD1d tetramers were provided by the NIH tetramer facility. 40 Natl acad sciences Washington 017sn