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 November 1, 2013; First published October 25, 2013
Citation Information: J Clin Invest. 2013;123(11):4923-4934. https://doi.org/10.1172/JCI69355.
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Category: 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 1

Treg cell–specific Itch deletion causes severe inflammation.

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Treg cell–specific Itch deletion causes severe inflammation. (A) Immunob...
(A) Immunoblot analysis of Itch in splenic CD4+YFP– conventional T cells (Tcov) and CD4+YFP+ Treg cells sorted from Itch+/+Foxp3Cre (Itch+/+) and Itchfl/flFoxp3Cre (Itchfl/fl) mice. Note that the upper blot is the same as that in Figure 7C. (B) Severe dermatitis in Itchfl/flFoxp3Cre mice at the age of 16 weeks. (C) Body weight of 4- to 12-week-old Itch+/+Foxp3Cre and Itchfl/flFoxp3Cre mice. (D) Kaplan-Meier survival curve of Itch+/+Foxp3Cre and Itchfl/flFoxp3Cre mice. (E) Splenomegaly and lymphadenopathy in Itchfl/flFoxp3Cre mice. (F) Spleen cellularity in Itch+/+Foxp3Cre mice (black circles) and Itchfl/flFoxp3Cre mice (white squares). (G) Representative H&E-stained tissue sections from 10-week-old Itch+/+Foxp3Cre and Itchfl/flFoxp3Cre mice. Original magnification, ×200 and ×100 (skin). (H) Inflammation scores. (I) Enhanced antigen-induced airway inflammation in Itchfl/flFoxp3Cre mice. Itch+/+Foxp3Cre and Itchfl/flFoxp3Cre mice (n = 3 each) were immunized i.p. with OVA in alum. Eighteen days later, mice were challenged by i.n. administration of OVA for 4 consecutive days. Total numbers of eosinophils (Eos), monocytes/macrophages (Mac), and lymphocytes (Lym) were calculated in BAL fluid 24 hours after the last OVA challenge. (J) Serum levels of OVA-specific IgE were measured by an ELISA assay. Data are compiled from two independent experiments with four mice per group. Error bars indicate the mean (± SD). *P < 0.05; **P < 0.01; ***P < 0.001 (unpaired 2-tailed Student’s t test).