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PU.1 Regulates TCR Expression by Modulating GATA-3 Activity¹

Hua-Chen Chang,^* Ling Han,^* Rukhsana Jabeen,^* Sebastian Carotta, Stephen L. Nutt, and Mark H. Kaplan^2*

^*Department of Pediatrics, Herman B Wells Center for Pediatric Research; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; and The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia

The Ets transcription factor PU.1 is a master regulator for the development of multiple lineages during hematopoiesis. The expression pattern of PU.1 is dynamically regulated during early T lineage development in the thymus. We previously revealed that PU.1 delineates heterogeneity of effector Th2 populations. In this study, we further define the function of PU.1 on the Th2 phenotype using mice that specifically lack PU.1 in T cells using an lck-Cre transgene with a conditional Sfpi1 allele (Sfpi1^lck–/–). Although deletion of PU.1 by the lck-Cre transgene does not affect T cell development, Sfpi1^lck–/– T cells have a lower activation threshold than wild-type T cells. When TCR engagement is limiting, Sfpi1^lck–/– T cells cultured in Th2 polarizing conditions secrete higher levels of Th2 cytokines and have greater cytokine homogeneity than wild-type cells. We show that PU.1 modulates the levels of TCR expression in CD4⁺ T cells by regulating the DNA-binding activity of GATA-3 and limiting GATA-3 regulation of TCR gene expression. GATA-3-dependent regulation of TCR expression is also observed in Th1 and Th2 cells. In CD4⁺ T cells, PU.1 expression segregates into subpopulations of cells that have lower levels of surface TCR, suggesting that PU.1 contributes to the heterogeneity of TCR expression. Thus, we have identified a mechanism whereby increased GATA-3 function in the absence of the antagonizing activity of PU.1 leads to increased TCR expression, a reduced activation threshold, and increased homogeneity in Th2 populations.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Award AI057459 (to M.H.K.) from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Mark H. Kaplan, Department of Pediatrics, Indiana University School of Medicine, HB Wells Center for Pediatric Research, 702 Barnhill Drive RI2600, Indianapolis, IN 46202. E-mail address: mkaplan2{at}iupui.edu

³ Abbreviations used in this paper: shRNA, short hairpin RNA; ChIP, chromatin immunoprecipitation assay; DAPA, DNA affinity precipitation assay; DN, double negative; E, enhancer; hCD4, human CD4; MFI, mean fluorescent intensity; siRNA, small interfering RNA.