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-γ (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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We thank A. Shaw, G. Petsko, M. Grusby and G. Lord for thoughtful review of the manuscript, and G. Petsko for advice on the statistical analysis. This work was supported by National Institutes of Health grants. R.M. is a recipient of the Kelli and Gerald Ford Irvington Institute Postdoctoral Fellowship.
The authors declare that they have no competing financial interests.
TCRß and IFNGR colocalize at the IS. (PDF 359 kb)
Neither IFNγ or Stat1 are required for IFNGR/TCR copolarization. (PDF 1103 kb)
Neither the presence of IL-4 nor absence of IFNγ induce IL-4R and TCR copolarization after Thp activation. (PDF 859 kb)
The polarization of IFNGR and TCR is not increased in IL-4-deficient BALB/c Thp. (PDF 471 kb)
Dynamics of Thp and DC coculture. (MP4 790 kb)
4D observation of the dynamics of Thp activation and receptor motility in the presence of OVA protein/peptide-loaded DC. (MOV 2296 kb)
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