title: Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation.
abstract: How a large number of cytokines differentially signal through a small number of signal transduction pathways is not well resolved. This is particularly true for IL-6 and IL-10, which act primarily through STAT3 yet induce dissimilar transcriptional programs leading alternatively to pro- and anti-inflammatory effects. Kinetic differences in signaling, sustained to IL-10 and transient to IL-6, are critical to this in macrophages. T cells are also key targets of IL-6 and IL-10, yet how differential signaling in these cells leads to divergent cellular fates is unclear. We show that, unlike for macrophages, signal duration cannot explain the distinct effects of these cytokines in T cells. Rather, naive, activated, activated-rested, and memory CD4(+) T cells differentially express IL-6 and IL-10 receptors in an activation state-dependent manner, and this impacts downstream cytokine effects. We show a dominant role for STAT3 in IL-6-mediated Th17 subset maturation. IL-10 cannot support Th17 differentiation because of insufficient cytokine receptivity rather than signal quality. Enforced expression of IL-10Rα on naive T cells permits an IL-10-generated STAT3 signal equivalent to that of IL-6 and equally capable of promoting Th17 formation. Similarly, naive T cell IL-10Rα expression also allows IL-10 to mimic the effects of IL-6 on both Th1/Th2 skewing and Tfh cell differentiation. Our results demonstrate a key role for the regulation of receptor expression rather than signal quality or duration in differentiating the functional outcomes of IL-6 and IL-10 signaling, and identify distinct signaling properties of these cytokines in T cells compared with myeloid cells.
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Lindsay L
authors.initials: LL
authors.lastname: Jones
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Rajshekhar
authors.initials: R
authors.lastname: Alli
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Bofeng
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105 terrence.geiger@stjude.org.
authors.forename: Terrence L
authors.initials: TL
authors.lastname: Geiger
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015870:Gene Expression; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D053698:Interleukin-6 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D053709:Interleukin-10 Receptor alpha Subunit; D015850:Interleukin-6; D053698:Interleukin-6 Receptor alpha Subunit; D050796:STAT3 Transcription Factor; D016753:Interleukin-10