TNF superfamily members play distinct roles in shaping the thymic stromal microenvironment. (April 2016)

• Record Type: Journal Article
• Authors: Bichele, Rudolf; Kisand, Kai; Peterson, Pärt; Laan, Martti
• Is Part Of: Molecular immunology. Volume 72(2016:Apr.)
• Page Start: 92
• Page End: 102
• Publication Date: 2016-04
• Subjects: Aire Autoimmune regulator -- αLTβR lymphotoxin beta receptor agonist antibody -- FTOC fetal thymic organ culture -- HVEM herpesvirus entry mediator -- IPA Ingenuity Pathway Analysis -- KO knockout -- LIGHT homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes -- LTβ(LTβR) lymphotoxin beta (receptor) -- NF-κB nuclear factor kappa-B -- qRT-PCR quantitative real-time polymerase chain reaction -- RANK (RANKL) (ligand of) receptor activator of nuclear factor kappa-B -- TCR T-cell receptor -- TEC (mTEC/cTEC) (medullary/cortical) thymic epithelial cell -- TFBS transcription factor binding site -- TNFα tumor necrosis factor alpha -- TNF(R)SF tumor necrosis factor (receptor) superfamily -- TRA tissue restricted antigen; Thymus -- Aire -- Chemokine -- RANK -- Lymphotoxin -- TNF; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2016.02.015
• Languages: English
• ISSNs: 0161-5890

Abstract

Highlights: RANKL specifically induces Aire and autoantigen expression in the thymic stroma. TNFα and LTβ induce the expression of key thymic chemokines. RANKL and LTβ work synergistically to establish the thymic microenvironment. Specific gene expression patterns may be attributable to differential NF-κB binding. Abstract: The differentiation and proper function of thymic epithelial cells (TECs) depend on various tumor necrosis factor superfamily (TNFSF) signals that are needed to maintain the thymic stromal microenvironment. Nevertheless, the direct transcriptional effects of these signals on TECs remain unclear. To address this issue, we stimulated murine embryonic thymus tissue with selected TNFSF ligands and performed a gene expression profiling study. We show that Aire expression is a direct and specific effect of RANKL stimulation, whereas LTβ and TNFα are major inducers of chemokines in the thymic stroma and we propose differential NF-κB binding as one possible cause of these gene expression patterns. Our work provides further insight into the complex molecular pathways that shape the thymic microenvironment and maintain central tolerance.