Premature expression of Foxp3 in double-negative thymocytes.

Melanie M Barra,Ann-Cathrin Hofer,David M Richards,Markus Feuerer,Michael Delacher,Antonio A Freitas

doi:10.1371/journal.pone.0127038

Melanie M Barra, Ann-Cathrin Hofer + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0127038

Copy DOI

Journal: PloS one	Publication Date: May 15, 2015
Citations: 3	License type: CC BY 4.0

Affiliation: German Cancer Research Center, Heidelberg University

Abstract

Peripheral immune regulation depends on the generation of thymic-derived regulatory T (tTreg) cells to maintain self-tolerance and to counterbalance overshooting immune responses. The expression of the Treg lineage defining transcription factor Foxp3 in developing tTreg cells depends on TCR signaling during the thymic selection process of these T cells. In this study, we surprisingly identify Foxp3+ immature thymocytes at the double-negative (DN) stage in transcription factor 7 (Tcf7)-deficient mice. These Foxp3+ cells did not express a TCR (β or γδ chains), CD3 or CD5 and therefore these cells were true DN cells. Further investigation of this phenomenon in a transgenic TCR model showed that Foxp3-expressing DN cells could not respond to TCR stimulation in vivo. These data suggest that Foxp3 expression in these DN cells occurred independently of TCR signaling. Interestingly, these Foxp3+ DN cells were located in a transition state between DN1 and DN2 (CD4-CD8-CD3-TCR-CD44highCD25low). Our results indicate that Tcf7 is involved in preventing the premature expression of Foxp3 in DN thymocytes.

Highlights

Regulatory T (Treg) cells are crucial to regulate immune responses, enforce immune homeostasis and maintain immune tolerance
Given the current understanding that forkhead box P3 (Foxp3) expression identifies committed Treg cells and, induction occurs after expression of a functional TCR, these results suggest that transcription factor 7 (Tcf7) plays a role in inhibiting Foxp3 expression in DN cells
Investigation of the role of Tcf7 in the development of thymic-derived Treg (tTreg) cells, using a Tcf7-deficient model, lead us to the surprising finding that Foxp3 was expressed at the DN stage in the absence of Tcf7

Summary

Introduction

Regulatory T (Treg) cells are crucial to regulate immune responses, enforce immune homeostasis and maintain immune tolerance. Mutations in their lineage-defining transcription factor forkhead box P3 (Foxp3) cause severe autoimmune disease in human and mouse [1]. At the CD4 and CD8 doublenegative (DN) stage, T cell precursors start to rearrange their TCRβ gene. Upon successful expression of a pre-TCR, the precursors develop into double positive (DP) cells, which express both CD4 and CD8 co-receptors. At the DP stage, the TCRα chain is rearranged and the functional TCRαβ is expressed on the surface together with the CD3 complex. Selection into the Treg lineage occurs during TCR-dependent positive and negative selection at the DP and CD4 single-positive (CD4SP) stage [3].

Methods

Results

Conclusion