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¹ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115
² Immune Disease Institute and ³ Department of Medicine, Harvard Medical School, Boston, MA 02115
⁴ Biological Engineering Division/Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
⁵ Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, A-1030 Vienna, Austria

CORRESPONDENCE Laurie. H. Glimcher: lglimche{at}hsph.harvard.edu

The antigen recognition interface formed by T helper precursors (Thps) and antigen-presenting cells (APCs), called the immunological synapse (IS), includes receptors and signaling molecules necessary for Thp activation and differentiation. We have recently shown that recruitment of the interferon- receptor (IFNGR) into the IS correlates with the capacity of Thps to differentiate into Th1 effector cells, an event regulated by signaling through the functionally opposing receptor to interleukin-4 (IL4R). Here, we show that, similar to IFN- ligation, TCR stimuli induce the translocation of signal transducer and activator of transcription 1 (STAT1) to IFNGR1-rich regions of the membrane. Unexpectedly, STAT1 is preferentially expressed, is constitutively serine (727) phosphorylated in Thp, and is recruited to the IS and the nucleus upon TCR signaling. IL4R engagement controls this process by interfering with both STAT1 recruitment and nuclear translocation. We also show that in cells with deficient Th1 or constitutive Th2 differentiation, the IL4R is recruited to the IS. This observation suggest that the IL4R is retained outside the IS, similar to the exclusion of IFNGR from the IS during IL4R signaling. This study provides new mechanistic cues for the regulation of lineage commitment by mutual immobilization of functionally antagonistic membrane receptors.

Abbreviations used: DP, double-positive thymocyte; ICS, intracellular cytokine staining; IFNGR, IFN- receptor; IS, immunological synapse; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; Thp, T helper precursor.

© 2009 Maldonado et al.
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