Development of promyelocytic leukemia zinc finger-expressing innate CD4 T cells requires stronger T-cell receptor signals than conventional CD4 T cells

Yu Qiao, Lingqiao Zhu, Hanief Sofi, Philip E. Lapinski, Reiko Horai, Kristen Mueller, Gretta L. Stritesky, Xi He, Hung Sia Teh, David L. Wiest, Dietmar J. Kappes, Philip D. King, Kristin A. Hogquist, Pamela L. Schwartzberg, Derek B. Sant'Angelo, Cheong Hee Chang

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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 γδ T cells, receive strong TCR signals during their development and that signaling requirements for the development and the effector functions are distinct.

Original languageEnglish (US)
Pages (from-to)16264-16269
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number40
DOIs
StatePublished - Oct 2 2012

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