Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways
| Autor: | Izumi Ohigashi, Joy A. Williams, Susan O. Sharrow, Anthony J. Adams, Richard J. Hodes, S. Rhiannon Jenkinson, Hyein Jeon, David Klug, Michael J. Kruhlak, Ronald E. Gress, Ellen R. Richie, Yousuke Takahama, Takeshi Nitta, Jingjing Zhang, Baishakhi Choudhury, Michael Eckhaus, Larry Granger |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male Adoptive cell transfer Immunology CD40 Ligand Receptors Antigen T-Cell chemical and pharmacologic phenomena T-Lymphocytes Regulatory Epithelium Article Mice CD28 Antigens medicine Immunology and Allergy Animals CD40 Antigens Mice Knockout Mice Inbred BALB C CD40 Thymocytes biology NF-kappa B CD28 hemic and immune systems Epithelial Cells NFKB1 Cell biology Up-Regulation Killer Cells Natural Thymocyte medicine.anatomical_structure Self Tolerance biology.protein B7-1 Antigen B7-2 Antigen Signal transduction CD80 Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 192(2) |
| ISSN: | 1550-6606 |
| Popis: | 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 single-positive 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 self-tolerance in thymocyte development. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|