Control of T helper cell differentiation through cytokine receptor inclusion in the immunological synapse.
The antigen recognition interface formed by T helper precursors (Thps) and antigen-presenting cells (APCs), called the immunological synapse (IS), includes receptors and signaling molecules necessary for Thp activation and differentiation. We have recently shown that recruitment of the interferon-gamma receptor (IFNGR) into the IS correlates with the capacity of Thps to differentiate into Th1 effector cells, an event regulated by signaling through the functionally opposing receptor to interleukin-4 (IL4R). Here, we show that, similar to IFN-gamma ligation, TCR stimuli induce the translocation of signal transducer and activator of transcription 1 (STAT1) to IFNGR1-rich regions of the membrane. Unexpectedly, STAT1 is preferentially expressed, is constitutively serine (727) phosphorylated in Thp, and is recruited to the IS and the nucleus upon TCR signaling. IL4R engagement controls this process by interfering with both STAT1 recruitment and nuclear translocation. We also show that in cells with deficient Th1 or constitutive Th2 differentiation, the IL4R is recruited to the IS. This observation suggest that the IL4R is retained outside the IS, similar to the exclusion of IFNGR from the IS during IL4R signaling. This study provides new mechanistic cues for the regulation of lineage commitment by mutual immobilization of functionally antagonistic membrane receptors.
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Roberto A
RA
Maldonado
Michelle A
MA
Soriano
L Carolina
LC
Perdomo
Kirsten
K
Sigrist
Darrell J
DJ
Irvine
Thomas
T
Decker
Laurie H
LH
Glimcher
D002454:Cell Differentiation; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation; D018448:Models, Immunological; D010047:Ovalbumin / Q000737:chemistry / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018121:Receptors, Cytokine / Q000276:immunology*; D017471:Receptors, Interferon / Q000276:immunology; D019948:Receptors, Interleukin-4 / Q000276:immunology; D013569:Synapses / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D000096743:Interferon gamma Receptor
D015847:Interleukin-4; D010047:Ovalbumin; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D018121:Receptors, Cytokine; D017471:Receptors, Interferon; D019948:Receptors, Interleukin-4; D000096743:Interferon gamma Receptor