Itch expression by Treg cells controls Th2 inflammatory responses
Hyung-seung Jin, … , Chris Elly, Yun-Cai Liu
Hyung-seung Jin, … , Chris Elly, Yun-Cai Liu
Published October 25, 2013
Citation Information: J Clin Invest. 2013;123(11):4923-4934. https://doi.org/10.1172/JCI69355.
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Research Article

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

Hyung-seung Jin, Yoon Park, Chris Elly, Yun-Cai Liu

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Figure 6

Itch-deficient Treg cells promoted higher Th2 responses in an OVA-induced airway inflammation model.

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Itch-deficient Treg cells promoted higher Th2 responses in an OVA-induce...
(A) Schematic immunization protocol. Animals were immunized with OVA in alum on days 0 and 7. FACS-sorted YFP+ Treg cells from OVA-sensitized Itch+/+Foxp3Cre or Itchfl/flFoxp3Cre mice were injected into the sensitized wild-type B6 mice on day 14. PBS was injected as a control. One day after Treg transfer, recipient mice were challenged i.n. with OVA protein for 5 consecutive days. (B) Total numbers of eosinophils, monocytes/macrophages, and lymphocytes were calculated in BAL fluid 48 hours after the last OVA challenge. (C) IL-4, IL-5, and IL-13 concentrations in BAL fluid were measured by ELISA. (D) Lung tissue sections were stained with H&E. Data are compiled from two independent experiments with two mice per group. Original magnification, ×200. Error bars indicate the mean (± SD). *P < 0.05 (unpaired 2-tailed Student’s t test).