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

Nature. 2004 Sep 30;431(7008):527-32. doi: 10.1038/nature02916. Epub 2004 Sep 22.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Lineage*
  • Cell Polarity
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Gene Deletion
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Interferon / metabolism
  • Receptors, Interleukin-4 / metabolism
  • STAT6 Transcription Factor
  • Th1 Cells / cytology
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Trans-Activators / metabolism

Substances

  • DNA-Binding Proteins
  • Rag2 protein, mouse
  • Receptors, Antigen, T-Cell
  • Receptors, Interferon
  • Receptors, Interleukin-4
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Trans-Activators
  • V(D)J recombination activating protein 2
  • interferon gamma receptor
  • Interleukin-4