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Τρίτη 1 Αυγούστου 2017

Analyses of a Mutant Foxp3 Allele Reveal BATF as a Critical Transcription Factor in the Differentiation and Accumulation of Tissue Regulatory T Cells

Publication date: Available online 1 August 2017
Source:Immunity
Author(s): Norihito Hayatsu, Takahisa Miyao, Masashi Tachibana, Ryuichi Murakami, Akihiko Kimura, Takako Kato, Eiryo Kawakami, Takaho A. Endo, Ruka Setoguchi, Hiroshi Watarai, Takeshi Nishikawa, Takuwa Yasuda, Hisahiro Yoshida, Shohei Hori
Foxp3 controls the development and function of regulatory T (Treg) cells, but it remains elusive how Foxp3 functions in vivo. Here, we established mouse models harboring three unique missense Foxp3 mutations that were identified in patients with the autoimmune disease IPEX. The I363V and R397W mutations were loss-of-function mutations, causing multi-organ inflammation by globally compromising Treg cell physiology. By contrast, the A384T mutation induced a distinctive tissue-restricted inflammation by specifically impairing the ability of Treg cells to compete with pathogenic T cells in certain non-lymphoid tissues. Mechanistically, repressed BATF expression contributed to these A384T effects. At the molecular level, the A384T mutation altered Foxp3 interactions with its specific target genes including Batf by broadening its DNA-binding specificity. Our findings identify BATF as a critical regulator of tissue Treg cells and suggest that sequence-specific perturbations of Foxp3-DNA interactions can influence specific facets of Treg cell physiology and the immunopathologies they regulate.

Graphical abstract

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Teaser

Hayatsu et al. report that an IPEX-associated Foxp3 mutation has expanded DNA recognition specificity and impairs tissue Treg cell fitness by repressing Batf. Their findings identify BATF as a critical regulator of tissue Treg cells and suggest that polymorphisms that impact Foxp3-DNA interactions may contribute to susceptibility to autoimmune disease.


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