title: Itch expression by Treg cells controls Th2 inflammatory responses.
abstract: Regulatory T (Treg) cells maintain immune homeostasis by limiting autoimmune and inflammatory responses. Treg differentiation, maintenance, and function are controlled by the transcription factor Foxp3. However, the exact molecular mechanisms underlying Treg cell regulation remain elusive. Here, we show that Treg cell-specific ablation of the E3 ubiquitin ligase Itch in mice caused massive multiorgan lymphocyte infiltration and skin lesions, chronic T cell activation, and the development of severe antigen-induced airway inflammation. Surprisingly, Foxp3 expression, homeostasis, and the in vitro and in vivo suppressive capability of Treg cells were not affected by Itch deficiency. We found that the expression of Th2 cytokines by Treg cells was increased in the absence of Itch. Fate mapping revealed that a fraction of Treg cells lost Foxp3 expression independently of Itch. However, Th2 cytokines were excessively augmented in Itch(-/-) Foxp3-negative "ex-Treg" cells without altering the percentage of conversion. Targeted knockdown of Th2 transcriptional regulators in Itch(-/-) Treg cells prevented Th2 cytokine production. The present study unveils a mechanism of Treg cell acquisition of Th2-like properties that is independent of Foxp3 function and Treg cell stability.
authors.forename: Hyung-seung
authors.initials: HS
authors.lastname: Jin
authors.forename: Yoon
authors.initials: Y
authors.lastname: Park
authors.forename: Chris
authors.initials: C
authors.lastname: Elly
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D051858:Forkhead Transcription Factors / Q000276:immunology; D015870:Gene Expression; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases