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The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2008 Apr 15; Vol. 180 (8), pp. 5384-92. - Publication Year :
- 2008
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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.
- Subjects :
- Animals
Clonal Deletion immunology
Cytokines immunology
Epithelial Cells cytology
Epithelial Cells immunology
Epithelial Cells metabolism
Gene Expression
Immune Tolerance
Lymphotoxin beta Receptor immunology
Lymphotoxin-alpha immunology
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Stromal Cells cytology
Stromal Cells immunology
Thymus Gland immunology
Transcription Factors immunology
AIRE Protein
Cytokines metabolism
Lymphotoxin beta Receptor metabolism
Lymphotoxin-alpha metabolism
Stromal Cells metabolism
Thymus Gland metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 180
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 18390720
- Full Text :
- https://doi.org/10.4049/jimmunol.180.8.5384