Cell：转录因子FoxP3的突变减缓关节炎加剧糖尿病

在多数免疫和炎症环境下，淋巴内稳态是由各种各样的调节性T细胞和转录因子FoxP3与特异的转录辅因子的相互作用来共同维持。

5月10日，Cell在线发表了哈佛医学院和凯特林癌症中心合作的一篇题为《An N-Terminal Mutation of the F oxp3 Transcription Factor Alleviates Arthritis but Exacerbates Diabetes》研究文章，发现转录因子FoxP3 N末端的一个突变可以减缓关节炎，反而却加剧糖尿病。

研究报道了FoxP3的一个普通插入突变（GFP-Foxp3）改变了分子相互作用：阻止了与HIF- 1a却提高了与IRF4的相互作用。这些调节性T细胞的侧面发生轻微地改变，导致过分地呈现依赖IRF4的转录子活性。GFP- FoxP3小鼠在保持调节性T细胞依赖IRF4的功能优先地抑制T细胞帮助B细胞、Th2和Th17等细胞类型的分化的同时，却对自身免疫病表现出相异的敏感性：在K/BxN模型中对抗体介导的关节炎起防护作用，而在NOD背景的小鼠中对糖尿病表现出更高的易感性。

FoxP3分子的相互作用可以影响调节性T细胞的特异子功能和它们调节的免疫疾病，最终导致相异的免疫调节。

doi.org/10.1016/j.immuni.2012.04.007

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An N-Terminal Mutation of the Foxp3 Transcription Factor Alleviates Arthritis but Exacerbates Diabetes

Jaime Darce1,Dipayan Rudra2,Li Li1,Junko Nishio1,Daniela Cipolletta1,Alexander Y. Rudensky2,Diane Mathis1,Christophe Benoist1

1 Division of Immunology， Department of Microbiology and Immunobiology， Harvard Medical School， Boston， MA 02115， USA

2 Howard Hughes Medical Institute and Immunology Program， Memorial Sloan-Kettering Cancer Center， New York， NY 10065， USA

Received 19 July 2011. Revised 12 January 2012. Accepted 4 April 2012. Available online 10 May 2012. Published online： May 10， 2012.

Summary

Maintenance of lymphoid homeostasis in a number of immunological and inflammatory contexts is served by a variety of regulatory T (Treg) cell subtypes and depends on interaction of the transcription factor FoxP3 with specific transcriptional cofactors. We report that a commonly used insertional mutant of FoxP3 (GFP-Foxp3) modified its molecular interactions， blocking HIF-1α but increasing IRF4 interactions. The transcriptional profile of these Treg cells was subtly altered， with an overrepresentation of IRF4-dependent transcripts. In keeping with IRF4-dependent function of Treg cells to preferentially suppress T cell help to B cells and Th2 and Th17 cell-type differentiation， GFP-FoxP3 mice showed a divergent susceptibility to autoimmune disease： protection against antibody-mediated arthritis in the K/BxN model， but greater susceptibility to diabetes on the NOD background. Thus， specific subfunctions of Treg cells and the immune diseases they regulate can be influenced by FoxP3's molecular interactions， which result in divergent immunoregulation.