title: Early growth response gene-2 controls IL-17 expression and Th17 differentiation by negatively regulating Batf.
abstract: Early growth response gene (Egr)-2 is important for the maintenance of T cell homeostasis and controls the development of autoimmune disease. However, the underlying mechanisms are unknown. We have now discovered that Egr-2, which is induced by TGF-β and IL-6, negatively regulates the expression of IL-17, but not IL-2 or IFN-γ, in effector T cells. In the absence of Egr-2, CD4 T cells produce high levels of Th17 cytokines, which renders mice susceptible to experimental autoimmune encephalomyelitis induction. T cells lacking Egr-2 show increased propensity for Th17, but not Th1 or Th2, differentiation. Control of IL-17 expression and Th17 differentiation by Egr-2 is due to inhibition of Batf, a transcription factor that regulates IL-17 expression and Th17 differentiation. Egr-2 interacts with Batf in CD4 T cells and suppresses its interaction with DNA sequences derived from the IL-17 promoter, whereas the activation of STAT3 and expression of retinoic acid-related orphan receptor γt are unchanged in Th17 cells in the absence of Egr-2. Thus, Egr-2 plays an important role to intrinsically control Th17 differentiation. We also found that CD4 T cells from multiple sclerosis patients have reduced expression of Egr-2 and increased expression of IL-17 following stimulation with anti-CD3 in vitro. Collectively, our results demonstrate that Egr-2 is an intrinsic regulator that controls Th17 differentiation by inhibiting Batf activation, which may be important for the control of multiple sclerosis development.
authors.affiliation: Blizard Institute of Cell and Molecular Science, Barts and London School of Medicine and Dentistry, London E1 2AD, United Kingdom.
authors.forename: Tizong
authors.initials: T
authors.lastname: Miao
authors.forename: Meera
authors.initials: M
authors.lastname: Raymond
authors.forename: Punamdip
authors.initials: P
authors.lastname: Bhullar
authors.forename: Emma
authors.initials: E
authors.lastname: Ghaffari
authors.forename: Alistair L J
authors.initials: AL
authors.lastname: Symonds
authors.forename: Ute C
authors.initials: UC
authors.lastname: Meier
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.forename: Suling
authors.initials: S
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D002454:Cell Differentiation / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology*; D051767:Early Growth Response Protein 2 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C431772:Batf protein, mouse; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17