title: Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6.
abstract: TGF-beta has pleiotropic effects on T cell differentiation that are determined by other cytokines in the local environment. Whereas IL-2 and TGF-beta induce naive T cells to become forkhead/winged helix transcription factor (Foxp3) positive regulatory cells (iTregs), the combination of IL-6 and TGF-beta induces IL-17-producing cells (Th17). Moreover, IL-6 can use TGF-beta produced by thymus-derived natural regulatory T cells (nTregs) to convert them to Th17 cells. In this study, we report a major difference between iTregs and nTregs. Treatment of iTregs with IL-6 did not affect Foxp3 expression, and their suppressive activity in vitro and in vivo was intact. To explain this difference between nTregs and iTregs, we found that IL-2 and TGF-beta down-regulate IL-6 receptor expression and IL-6 signaling. The resistance of iTregs to Th17 conversion suggests that they can function more effectively than nTregs in an inflammatory milieu and emphasizes the central role of IL-2 in combination with TGF-beta to maintain immunologic homeostasis.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.forename: Juhua
authors.initials: J
authors.lastname: Wang
authors.forename: David A
authors.initials: DA
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019947:Receptors, Interleukin-6 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D016212:Transforming Growth Factor beta