The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells

Seach, Natalie, Ueno, Tomoo, Fletcher, Anne L., Lowen, Tamara, Mattesich, Monika, Engwerda, Christian R., Scott, Hamish S., Ware, Carl F., Chidgey, Ann P., Gray, Daniel H. D. and Boyd, Richard L. (2008) The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells. Journal of Immunology, 180 8: 5384-5392.

Author Seach, Natalie
Ueno, Tomoo
Fletcher, Anne L.
Lowen, Tamara
Mattesich, Monika
Engwerda, Christian R.
Scott, Hamish S.
Ware, Carl F.
Chidgey, Ann P.
Gray, Daniel H. D.
Boyd, Richard L.
Title The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
1550-6606
Publication date 2008-04-15
Sub-type Article (original research)
Volume 180
Issue 8
Start page 5384
End page 5392
Total pages 9
Place of publication Bethesda, MD, United States
Publisher American Association of Immunologists
Language eng
Formatted 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 LTβR 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. LTβR 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 LTβR signals were important for TRA expression in a distinct population of mTEC characterized by low levels of MHC class II (mTEClow), 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 LTα1β2-LTβR signaling in the maintenance of the thymic microenvironments, specifically by regulating TRA and chemokine expression in mTEClow for efficient induction of central tolerance.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Tue, 08 Nov 2011, 12:20:29 EST by Matthew Lamb on behalf of School of Medicine