title: A role for the immunological synapse in lineage commitment of CD4 lymphocytes.
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.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115-6017, USA.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Maldonado
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
authors.forename: Robert
authors.initials: R
authors.lastname: Schreiber
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D019070:Cell Lineage; D016764:Cell Polarity; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D017353:Gene Deletion; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D050800:STAT6 Transcription Factor; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D004268:DNA-Binding Proteins; D015847:Interleukin-4; D011948:Receptors, Antigen, T-Cell; D017471:Receptors, Interferon; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C499308:Rag2 protein, mouse; C494100:Stat6 protein, mouse; C064655:V(D)J recombination activating protein 2