1. Antigen Recognition by Autoreactive CD4+ Thymocytes Drives Homeostasis of the Thymic Medulla.
- Author
-
Irla, Magali, Guerri, Lucia, Guenot, Jeanne, Sergé, Arnauld, Lantz, Olivier, Liston, Adrian, Imhof, Beat A., Palmer, Ed, and Reith, Walter
- Subjects
IMMUNOGLOBULINS ,HOMEOSTASIS ,T cell receptors ,EPITHELIAL cells ,THYMOCYTES ,MEDICAL research - 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 a 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. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
- View/download PDF