Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways

Joy A. Williams, Jingjing Zhang, Hyein Jeon, Takeshi Nitta, Izumi Ohigashi, David Klug, Michael J. Kruhlak, Baishakhi Choudhury, Susan O. Sharrow, Larry Granger, Anthony Adams, Michael A. Eckhaus, S. Rhiannon Jenkinson, Ellen R. Richie, Ronald E. Gress, Yousuke Takahama, Richard J. Hodes*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

30 Citations (Scopus)

Abstract

A critical process during thymic development of the T cell repertoire is the induction of self-tolerance. Tolerance in developing T cells is highly dependent on medullary thymic epithelial cells (mTEC), and mTEC development in turn requires signals from mature single-positive thymocytes, a bidirectional relationship termed thymus crosstalk. We show that CD28-CD80/86 and CD40- CD40L costimulatory interactions, which mediate negative selection and self-tolerance, upregulate expression of LTα, LTβ, and receptor activator for NF-κB in the thymus and are necessary for medullary development. Combined absence of CD28-CD80/86 and CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the absence of singlepositive thymocytes. This requirement for costimulatory signaling is maintained even in a TCR transgenic model of high-affinity TCR-ligand interactions. CD4 thymocytes maturing in the altered thymic epithelial environment of CD40/CD80/86 knockout mice are highly autoreactive in vitro and are lethal in congenic adoptive transfer in vivo, demonstrating a critical role for these costimulatory pathways in self-tolerance as well as thymic epithelial development. These findings demonstrate that cooperativity between CD28-CD80/86 and CD40-CD40L pathways is required for normal medullary epithelium and for maintenance of selftolerance in thymocyte development.

Original languageEnglish
Pages (from-to)630-640
Number of pages11
JournalJournal of Immunology
Volume192
Issue number2
DOIs
Publication statusPublished - 15 Jan 2014

Fingerprint Dive into the research topics of 'Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways'. Together they form a unique fingerprint.

Cite this