1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115-6017, USA
2. Biological Engineering Division/Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
3. Department of Pathology and Immunology, Center for Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA
4. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Laurie H. Glimcher^1,4 Email: lglimche@hsph.harvard.edu

Abstract

Activation of the naive T-helper lymphocyte (Thp) directs it down one of two major developmental pathways called Th1 and Th2. Signals transmitted by T cell, co-stimulatory and cytokine receptors control Thp lineage commitment but the mechanism by which these signals are integrated remains a mystery. The interferon- (IFNGR) and interleukin 4 (IL-4R) cytokine receptors, in particular, direct the earliest stages of T-helper commitment. Here we report that on engagement of the T-cell receptor (TCR) on Thp cells, rapid co-polarization of IFNGR with the TCR occurs within the developing immunological synapse. Thp cells from the intrinsically Th1-like C57BL/6 mouse strain have significantly more receptor co-polarization than Th2-prone BALB/c Thp cells. Remarkably, in the presence of IL-4, a cytokine required for Th2 differentiation, IFNGR co-polarization with TCR is prevented. This inhibition depends on Stat6, the transcription factor downstream of IL-4R that is required for Th2 differentiation. This cytokine receptor crossregulation provides an explanation for the effect of IL-4 in inhibiting Th1 differentiation. These observations suggest a scenario in which physical co-polarization of critical receptors directs the fate of the naive Thp, and offer a novel function for the immunological synapse in directing cell differentiation. They further suggest a new mechanism of membrane-bound signalling control by the physical disruption of large receptor-rich domains on signalling through a functionally antagonistic receptor.

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