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

• DOI: 10.1371/journal.pone.0052591
• Publication Date: 2012-12-27T23:53:28Z
• Authors: Magali Irla; Lucia Guerri; Jeanne Guenot; Arnauld Sergé; Olivier Lantz; Adrian Liston; Beat A. Imhof; Ed Palmer; Walter Reith
• Keywords: Male; 0301 basic medicine; Thymus Gland/cytology/growth & development/immunology; info:eu-repo/classification/ddc/616.07; Science; Antigens, CD4/metabolism; CD40 Ligand; CD40 Ligand/metabolism; Gene Expression; ddc:616.07; Lymphotoxin beta Receptor/metabolism; Autoantigens; Tissue Culture Techniques; Mice; 03 medical and health sciences; Autoantigens/immunology; Lymphotoxin beta Receptor; Animals; Homeostasis; CD40 Antigens; Lymphotoxin-alpha; Antigens, CD40/metabolism; Body Patterning; Cell Proliferation; Mice, Knockout; Thymocytes; Receptor Activator of Nuclear Factor-kappa B; Q; R; Epithelial Cells; Thymocytes/immunology/metabolism/physiology; [SDV] Life Sciences [q-bio]; Mice, Inbred C57BL; CD4 Antigens; Medicine; Female; Lymphotoxin-alpha/genetics/metabolism; Epithelial Cells/metabolism/physiology; Receptor Activator of Nuclear Factor-kappa B/metabolism; Research Article; Signal Transduction

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.