title: IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1.
abstract: Foxp3(+) regulatory T cells (Tregs) play essential roles in maintaining the immune balance. Although the majority of Tregs are formed in the thymus, increasing evidence suggests that induced Tregs (iTregs) may be generated in the periphery from naive cells. However, unlike in the murine system, significant controversy exists regarding the suppressive capacity of these iTregs in humans, especially those generated in vitro in the presence of TGF-β. Although it is well known that IL-10 is an important mediator of Treg suppression, the action of IL-10 on Tregs themselves is less well characterized. In this article, we show that the presence of IL-10, in addition to TGF-β, leads to increased expansion of Foxp3(+) iTregs with enhanced CTLA-4 expression and suppressive capability, comparable to that of natural Tregs. This process is dependent on IL-10R-mediated STAT3 signaling, as supported by the lack of an IL-10 effect in patients with IL-10R deficiency and dominant-negative STAT3 mutation. Additionally, IL-10-induced inhibition of Akt phosphorylation and subsequent preservation of Foxo1 function are critical. These results highlight a previously unrecognized function of IL-10 in human iTreg generation, with potential therapeutic implications for the treatment of immune diseases, such as autoimmunity and allergy.
authors.affiliation: Charles Perkins Centre Nepean, The University of Sydney, Kingswood, New South Wales 2751, Australia; Department of Allergy and Immunology, Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Hsu
authors.affiliation: Charles Perkins Centre Nepean, The University of Sydney, Kingswood, New South Wales 2751, Australia;
authors.forename: Brigitte
authors.initials: B
authors.lastname: Santner-Nanan
authors.affiliation: Charles Perkins Centre Nepean, The University of Sydney, Kingswood, New South Wales 2751, Australia;
authors.forename: Mingjing
authors.initials: M
authors.lastname: Hu
authors.affiliation: Charles Perkins Centre Nepean, The University of Sydney, Kingswood, New South Wales 2751, Australia;
authors.forename: Kristen
authors.initials: K
authors.lastname: Skarratt
authors.affiliation: Department of Gastroenterology, Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia.
authors.forename: Cheng Hiang
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Gastroenterology, Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Stormon
authors.affiliation: Department of Allergy and Immunology, Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia; and.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.affiliation: Charles Perkins Centre Nepean, The University of Sydney, Kingswood, New South Wales 2751, Australia;
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Fuller
authors.affiliation: Charles Perkins Centre Nepean, The University of Sydney, Kingswood, New South Wales 2751, Australia; Ralph.Nanan@sydney.edu.au.
authors.forename: Ralph
authors.initials: R
authors.lastname: Nanan
mesh_terms: D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D008297:Male; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D053701:Receptors, Interleukin-10 / Q000172:deficiency / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D051057:Proto-Oncogene Proteins c-akt