IL-27 inhibits the development of regulatory T cells via STAT3.
Regulatory CD4+ T cells are important for the homeostasis of the immune system and their absence correlates with autoimmune disorders. Here, we investigate the capacity of IL-27, a cytokine with pro- and anti-inflammatory properties, to regulate the generation of transforming growth factor beta (TGFbeta)-inducible forkhead box P3 (Foxp3)-positive regulatory T (Treg) cells. Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3, CD25 and CTLA-4 (CD152) expression as well as the suppressive function. In contrast to TGFbeta-induced Treg cells, the cells generated after differentiation in the presence of TGFbeta and IL-27 maintained the ability for IL-2 and tumour necrosis factor alpha (TNFalpha) production. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA), while STAT1-dependent signals seemed to oppose the STAT3 signals. In turn, TGFbeta blocked IL-27-induced T(h)1 differentiation. Thus, IL-27 and TGFbeta mutually control their effects on CD4+ T-cell differentiation, whereby IL-27 favours inflammatory conditions through a STAT3-dependent inhibition of Treg generation.
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C486767:Il27 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D053773:Transforming Growth Factor beta1