title: The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells.
abstract: Medullary thymic epithelial cells (mTEC) play an important and unique role in central tolerance, expressing tissue-restricted Ags (TRA) which delete thymocytes autoreactive to peripheral organs. Since deficiencies in this cell type or activity can lead to devastating autoimmune diseases, it is important to understand the factors which regulate mTEC differentiation and function. Lymphotoxin (LT) ligands and the LTbetaR have been recently shown to be important regulators of mTEC biology; however, the precise role of this pathway in the thymus is not clear. In this study, we have investigated the impact of this signaling pathway in greater detail, focusing not only on mTEC but also on other thymic stromal cell subsets. LTbetaR expression was found in all TEC subsets, but the highest levels were detected in MTS-15(+) thymic fibroblasts. Rather than directing the expression of the autoimmune regulator Aire in mTEC, we found LTbetaR signals were important for TRA expression in a distinct population of mTEC characterized by low levels of MHC class II (mTEC(low)), as well as maintenance of MTS-15(+) fibroblasts. In addition, thymic stromal cell subsets from LT-deficient mice exhibit defects in chemokine production similar to that found in peripheral lymphoid organs of Lta(-/-) and Ltbr(-/-) mice. Thus, we propose a broader role for LTalpha1beta2-LTbetaR signaling in the maintenance of the thymic microenvironments, specifically by regulating TRA and chemokine expression in mTEC(low) for efficient induction of central tolerance.
authors.affiliation: Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Seach
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ueno
authors.forename: Anne L
authors.initials: AL
authors.lastname: Fletcher
authors.forename: Tamara
authors.initials: T
authors.lastname: Lowen
authors.forename: Monika
authors.initials: M
authors.lastname: Mattesich
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.forename: Ann P
authors.initials: AP
authors.lastname: Chidgey
authors.forename: Daniel H D
authors.initials: DH
authors.lastname: Gray
authors.forename: Richard L
authors.initials: RL
authors.lastname: Boyd
mesh_terms: D000818:Animals; D017637:Clonal Deletion / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D007108:Immune Tolerance; D053259:Lymphotoxin beta Receptor / Q000276:immunology / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D016207:Cytokines; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D014157:Transcription Factors; D000096927:AIRE Protein