title: Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways.
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 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.
authors: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Joy A
authors: JA
authors: Williams
authors: Jingjing
authors: J
authors: Zhang
authors: Hyein
authors: H
authors: Jeon
authors: Takeshi
authors: T
authors: Nitta
authors: Izumi
authors: I
authors: Ohigashi
authors: David
authors: D
authors: Klug
authors: Michael J
authors: MJ
authors: Kruhlak
authors: Baishakhi
authors: B
authors: Choudhury
authors: Susan O
authors: SO
authors: Sharrow
authors: Larry
authors: L
authors: Granger
authors: Anthony
authors: A
authors: Adams
authors: Michael A
authors: MA
authors: Eckhaus
authors: S Rhiannon
authors: SR
authors: Jenkinson
authors: Ellen R
authors: ER
authors: Richie
authors: Ronald E
authors: RE
authors: Gress
authors: Yousuke
authors: Y
authors: Takahama
authors: Richard J
authors: RJ
authors: Hodes
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology; D004848:Epithelium / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D060168:Thymocytes / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D023201:CD40 Ligand