A role for the immunological synapse in lineage commitment of CD4 lymphocytes

Nature
Roberto A MaldonadoL H Glimcher

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-gamma (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 ...Continue Reading

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