The transcription factor Batf3 inhibits the differentiation of regulatory T cells in the periphery

Wonyong Lee,Hyeong Su Kim,Gap Ryol Lee,Soo Seok Hwang

doi:10.1038/emm.2017.157

Abstract

Naive CD4 T cells activated by antigen-presenting cells (APCs) undergo terminal differentiation in the periphery. Multiple mechanisms determine their fates, that is, whether they differentiate into conventional T (Tconv) cells or regulatory T (Treg) cells. The key event during Treg generation is expression of the transcription factor Foxp3, which is the lineage-determining regulator for Treg differentiation and function. Here we show that the transcription factor Batf3 acts as a fate-decision factor with respect to Tconv versus Tregs by restraining Treg differentiation. Batf3 was preferentially expressed in effector CD4 T cells but not in Treg cells, and ectopic expression of Batf3 inhibited Foxp3 induction. Batf3-deficient CD4 T cells favorably differentiated into Treg cells in vitro and in colonic lamina propria. Batf3 KO mice also showed enhanced Treg function in gut-associated immune disease models (for example, ovalbumin tolerance and inflammatory bowel disease models). Batf3 bound to the CNS1 region of the Foxp3 locus and reduced expression of the gene. Thus, Batf3 is a transcriptional suppressor of Treg differentiation.

Highlights

Thymus-derived Treg cells differentiate during thymic development, while peripherally derived Treg cells originate from naive CD4 T cells in the periphery.[1,2,3,4]
Differential expression of Batf[3] between Teff and Treg cells To identify novel T cell fate-determining factors, we first performed microarray analysis to identify differential expression of transcription factors between Treg and Tconv cells, reasoning that negative regulators would be expressed at low levels in Treg cells
When we measured the kinetics of Batf[3] expression by quantitative RT-PCR at different time points after T-cell activation, we found that the amount of Batf[3] transcript in Teff cells gradually increased; it remained low in Treg cells

Summary

Introduction

Foxp[3] determines the differentiation and maintenance of Treg cells.[6,7] Disruption of Foxp[3] expression hampers Treg differentiation, and Foxp[3] deficiency is linked to fatal autoimmunity in both mice and humans. The scurfy mutation or experimental deletion of the Foxp[3] gene causes fatal autoimmune diseases. Mutation of the human FOXP3 gene leads to the development of immune dysregulation polyendocrinopathy enteropathy X-linked syndrome.[8,9,10,11]

Methods

Results

Conclusion