Redefining thymus medulla specialization for central tolerance.

Emilie J Cosway,Alexei V Tumanov,Andrea J White,Beth Lucas,William E Jenkinson,Kieran D James,Sonia M Parnell,Graham Anderson,Manuela Carvalho-Gaspar

doi:10.1084/jem.20171000

Abstract

During αβT cell development, the thymus medulla represents an essential microenvironment for T cell tolerance. This functional specialization is attributed to its typical organized topology consisting of a branching structure that contains medullary thymic epithelial cell (mTEC) networks to support negative selection and Foxp3+ T-regulatory cell (T-reg) development. Here, by performing TEC-specific deletion of the thymus medulla regulator lymphotoxin β receptor (LTβR), we show that thymic tolerance mechanisms operate independently of LTβR-mediated mTEC development and organization. Consistent with this, mTECs continue to express Fezf2 and Aire, regulators of intrathymic self-antigens, and support T-reg development despite loss of LTβR-mediated medulla organogenesis. Moreover, we demonstrate that LTβR controls thymic tolerance by regulating the frequency and makeup of intrathymic dendritic cells (DCs) required for effective thymocyte negative selection. In all, our study demonstrates that thymus medulla specialization for thymic tolerance segregates from medulla organogenesis and instead involves LTβR-mediated regulation of the thymic DC pool.

Highlights

The thymus generates αβT cells that respond to foreign antigens presented by self-MHC molecules (Boehm, 2008)
thymic epithelial cell (TEC)-restricted deletion of lymphotoxin β receptor (LTβR) dissociates medulla topology from tolerance induction Normal programs of medullary thymic epithelial cell (mTEC) development and medulla formation are seen to be essential for the specialized function of this site.The TNF receptor superfamily (TNFRSF) member LTβR is a key regulator of thymic microenvironments and intrathymic tolerance, and its expression is readily detectable in multiple TEC subsets (Fig. 1 A)
LTβR expression by EpCAM1+ TEC was absent in Ltbr−/− mice and LTβRTEC mice (Fig. 1 B), demonstrating the effectiveness of this model to examine the relationship between medulla function and tolerance

Summary

Introduction

The thymus generates αβT cells that respond to foreign antigens presented by self-MHC molecules (Boehm, 2008). LTβR expression by EpCAM1+ TEC was absent in Ltbr−/− mice and LTβRTEC mice (Fig. 1 B), demonstrating the effectiveness of this model to examine the relationship between medulla function and tolerance.

Results

Conclusion