Antigen Recognition By Autoreactive Cd4+ Thymocytes Drives Homeostasis Of The Thymic Medulla

Arnauld Sergé,Magali Irla,Beat A. Imhof,Olivier Lantz,Walter Reith,Jeanne Guenot,Lucia Guerri,Ed Palmer,Adrian Liston

doi:10.1371/journal.pone.0052591

Arnauld Sergé, Magali Irla + Show 7 more

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https://doi.org/10.1371/journal.pone.0052591

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Abstract

The thymic medulla is dedicated for purging the T-cell receptor (TCR) repertoire of self-reactive specificities. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process because they express numerous peripheral tissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single-positive (SP) thymocytes, the mechanisms underlying this requirement are incompletely understood. We demonstrate here that conventional SP CD4+ thymocytes bearing autoreactive TCRs drive a homeostatic process that fine-tunes medullary plasticity in adult mice by governing the expansion and patterning of the medulla. This process exhibits strict dependence on TCR-reactivity with self-antigens expressed by mTECs, as well as engagement of the CD28-CD80/CD86 costimulatory axis. These interactions induce the expression of lymphotoxin α in autoreactive CD4+ thymocytes and RANK in mTECs. Lymphotoxin in turn drives mTEC development in synergy with RANKL and CD40L. Our results show that Ag-dependent interactions between autoreactive CD4+ thymocytes and mTECs fine-tune homeostasis of the medulla by completing the signaling axes implicated in mTEC expansion and medullary organization.

Highlights

The thymus ensures the generation of a self-tolerant T cell receptor (TCR) repertoire
Tolerance to self-antigens (Ags) is established in the medulla, a specialized microenvironment mainly composed of medullary thymic epithelial cells and dendritic cells (DCs). mTECs are critical for inducing selftolerance because they constitute a thymic reservoir of numerous peripheral tissue-restricted self-Ags (TRAs) [1,2]
Thymic sections from wild-type (WT), b2m2/2, H2-Aa2/2 and TCRa2/2 mice were stained with antibodies directed against the cortical TEC marker keratin 8 (K8) and the mTEC marker keratin 14 (K14) (Figure 1A)

Summary

Introduction

The thymus ensures the generation of a self-tolerant T cell receptor (TCR) repertoire. Tolerance to self-antigens (Ags) is established in the medulla, a specialized microenvironment mainly composed of medullary thymic epithelial cells (mTECs) and dendritic cells (DCs). MTECs are critical for inducing selftolerance because they constitute a thymic reservoir of numerous peripheral tissue-restricted self-Ags (TRAs) [1,2]. MTECs can present TRAs to autoreactive CD8+ and CD4+ SP thymocytes to promote their deletion or the generation of natural regulatory T cells [4,5,6]. TRAs expressed by mTECs are captured by thymic DCs, which help to purge the thymocyte repertoire of autoreactive TCR specificities [4]. The medulla ensures the establishment of T-cell tolerance via tight collaboration between mTECs and DCs [8]

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