The composition and signaling of the IL-35 receptor are unconventional.
Interleukin 35 (IL-35) belongs to the IL-12 family of heterodimeric cytokines but has a distinct functional profile. IL-35 suppresses T cell proliferation and converts naive T cells into IL-35-producing induced regulatory T cells (iTr35 cells). Here we found that IL-35 signaled through a unique heterodimer of receptor chains IL-12Rβ2 and gp130 or homodimers of each chain. Conventional T cells were sensitive to IL-35-mediated suppression in the absence of one receptor chain but not both receptor chains, whereas signaling through both chains was required for IL-35 expression and conversion into iTr35 cells. Signaling through the IL-35 receptor required the transcription factors STAT1 and STAT4, which formed a unique heterodimer that bound to distinct sites in the promoters of the genes encoding the IL-12 subunits p35 and Ebi3. This unconventional mode of signaling, distinct from that of other members of the IL-12 family, may broaden the spectrum and specificity of IL-35-mediated suppression.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Lauren W
LW
Collison
Greg M
GM
Delgoffe
Clifford S
CS
Guy
Kate M
KM
Vignali
Vandana
V
Chaturvedi
DeLisa
D
Fairweather
Abhay R
AR
Satoskar
K Christopher
KC
Garcia
Christopher A
CA
Hunter
Charles G
CG
Drake
Peter J
PJ
Murray
Dario A A
DA
Vignali
D000818:Animals; D050822:Cytokine Receptor gp130 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D018123:Receptors, Interleukin / Q000737:chemistry / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology; D050797:STAT4 Transcription Factor / Q000276:immunology; D015398:Signal Transduction
C494200:Il6st protein, mouse; D007378:Interleukins; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; C571100:interleukin 35 receptor, mouse; C569375:interleukin-35, mouse; D050822:Cytokine Receptor gp130