Regulatory T cell Itch reins in Th2 inflammation.
Regulatory T cell Itch reins in Th2 inflammation.
复制标题
调节性 T 细胞痒可抑制 Th2 炎症。
DOI：
10.1038/cmi.2013.63
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发表时间：
2014
影响因子：
24.1
通讯作者：
D'Alessio,FrancoR
中科院分区：
文献类型：
--
作者：
Singer,BenjaminD;D'Alessio,FrancoR
Type 2 T helper (Th2) inflammation underlies common clinical disorders such as asthma, eczema and other atopic diseases. CD4+ regulatory T cells (Tregs) suppress over-exuberant immune responses in a variety of inflammatory microenvironments, including Th2 conditions. The transcription factor forkhead box protein 3 (Foxp3) controls Treg development, function and maintenance; however, mechanisms through which Tregs mitigate immune activation during different inflammatory situations remain largely unknown. In their recent article, Jin et al. report that Itch, an E3 ubiquitin ligase, is required to prevent Tregs from acquiring Th2-like phenotype and function. 1 The authors created a novel Treg-specific Itch-deficient mouse (Itchfl/flFoxp3Cre) that enabled careful examination of Treg Itch in controlling Th2 inflammatory responses. General Treg suppressive mechanisms involve contact-dependent inhibitory cell surface receptors (CTLA-4), competition for growth factors (CD25), hydrolysis of extracellular nucleotides (CD39, CD73) and induction of cell death (granzyme secretion). 2 Additionally, Tregs suppress T cell skewing by acquiring specific T effector transcriptional programs that permit homing to a particular inflammatory microenvironment. Expression of the transcription factors T-bet, Irf4 and STAT3 regulate Treg suppressive activity in Th1, Th2 and Th17 inflammation, respectively (Table 1). 3–5 Indeed, Tregspecific Irf4 knockout mice have dysregulated Th2 responses. However, we have limited data on the specific molecular pathways that Tregs employ to control Th2 inflammation.Ubiquitin conjugation is a key immune regulatory mechanism. Post-translational ubiquitination leads to differential consequences for the substrate protein and results in diverse cellular responses. 6 Itch is a HECT (homologous to E6-associated protein C terminus)-type E3 ubiquitin ligase involved in immune regulation. Itch knockout (ItchJ/J) mice develop skin-scratching, enlarged lymph nodes and spleen and inflammation of the lungs and gut. 7 CD4+ T cells in these mice produce Th2 cytokines, 8 and this Th2 skewing has been linked to the inability of naıve CD4+ T cells to convert into inducible Tregs. The Itchfl/flFoxp3Cre mouse allowed Jin et al. to study Itch in thymus-derived natural Tregs. The authors provide convincing evidence that Treg-specific Itch critically limits Th2 inflammation. Itchfl/flFoxp3Cre mice were normal at birth, but spontaneously developed systemic Th2 inflammation characterized by early mortality, as well as skin-scratching, splenomegaly, lymphadenopathy, and splenic, pulmonary, dermal, gastric and hepatic inflammation by 6 weeks of age. They also demonstrated hyper-responsiveness to an antigen-induced airway inflammation model of asthma (ovalbumin immunization and challenge). Notably, while wildtype Treg adoptive transfer ameliorated
