Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6.
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.
Zheng
Song Guo
SG
Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA 90033, USA.
Wang
Juhua
J
Horwitz
David A
DA
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*
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