Foxp1 is critical for the maintenance of regulatory T-cell homeostasis and suppressive function.

Jiazi Ren,Yuanhua Liu,Hui Hu,Pei Hao,Lei Han,Haikun Wang,Xiaoxue Deng,Bin Li,Qiuyue Liu,Xiaoming Feng,Jinyi Tang,Paula M Oliver

doi:10.1371/journal.pbio.3000270

Abstract

Regulatory T (Treg) cells play central roles in maintaining immune homeostasis and self-tolerance. However, the molecular mechanisms underlying Treg cell homeostasis and suppressive function are still not fully understood. Here, we report that the deletion of another P subfamily members of the forkhead box (Foxp) subfamily member Foxp1 in Treg cells led to increased numbers of activated Treg (aTreg) cells at the expense of quiescent Treg cells, and also resulted in impaired Treg suppressive function. Mice with Foxp1-deficient Treg cells developed spontaneous inflammatory disease with age; they also had more severe inflammatory disease in colitis and experimental autoimmune encephalomyelitis (EAE) models. Mechanistically, we found that Foxp1 bound to the conserved noncoding sequence 2 (CNS2) element of the Foxp3 locus and helped maintain Treg suppressive function by stabilizing the Foxp3 expression. Furthermore, we found that Foxp1 and Foxp3 coordinated the regulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression levels. Taken together, our study demonstrates that Foxp1 plays critical roles in both maintaining Treg cell quiescence during homeostasis and regulating Treg suppressive function.

Highlights

Regulatory T (Treg) cells are a subset of CD4+ T cells of vital importance in the maintenance of immunological self-tolerance and T-cell homeostasis [1,2]
We have shown that forkhead box P1 (Foxp1) has no effect on the generation of Treg cells in the thymus of Foxp1f/fCD4Cre mice [30], in which Foxp1 is deleted at the double-positive (DP) thymocyte stage
We found that resting Treg (rTreg) cells expressed high levels of the full-length Foxp1 isoform, Foxp1A, and low levels of the short isoform Foxp1D (Fig 1A), which resembles the Foxp1 expression in conventional naive CD4+ T cells, suggesting that Foxp1 may play an important role in maintaining the quiescent state of rTreg cells, like its role in naive CD4+ T

Summary

Introduction

Regulatory T (Treg) cells are a subset of CD4+ T cells of vital importance in the maintenance of immunological self-tolerance and T-cell homeostasis [1,2]. Like conventional CD4+ T cells, Treg cells in the periphery have subpopulations with different functions. Based on the expression levels of cell surface markers CD44 and CD62L, Treg cells can be divided into CD44lowCD62Lhigh resting Treg (rTreg) and CD44highCD62Llow activated Treg (aTreg) cells [3,4]. RTreg cells are more quiescent Treg cells in the secondary lymphoid tissues, where. Sciences (XDB29030103, HW), the National Natural Science Foundation of China (81273217, XF), China Young scholar 1000-Talent Program (HW), the National Natural Science Foundation of China (31570886, HW), and US National Institutes of Health (AI095439 and AI103162, HH) Based on the expression levels of cell surface markers CD44 and CD62L, Treg cells can be divided into CD44lowCD62Lhigh resting Treg (rTreg) and CD44highCD62Llow activated Treg (aTreg) cells [3,4]. rTreg cells are more quiescent Treg cells in the secondary lymphoid tissues, where

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