Overexpression of lymphotoxin in T cells induces fulminant thymic involution

Heikenwalder, Mathias; Prinz, Marco; Zeller, Nicolas; Lang, Karl S; Junt, Tobias; Rossi, Simona; Tumanov, Alexei; Schmidt, Hauke; Priller, Josef; Flatz, Lukas; Rülicke, Thomas; Macpherson, Andrew J; Holländer, Georg A; Nedospasov, Sergei A; Aguzzi, Adriano (2008). Overexpression of lymphotoxin in T cells induces fulminant thymic involution. American journal of pathology, 172(6), pp. 1555-70. New York, N.Y.: Elsevier 10.2353/ajpath.2008.070572

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Activated lymphocytes and lymphoid-tissue inducer cells express lymphotoxins (LTs), which are essential for the organogenesis and maintenance of lymphoreticular microenvironments. Here we describe that T-cell-restricted overexpression of LT induces fulminant thymic involution. This phenotype was prevented by ablation of the LT receptors tumor necrosis factor receptor (TNFR) 1 or LT beta receptor (LTbetaR), representing two non-redundant pathways. Multiple lines of transgenic Ltalphabeta and Ltalpha mice show such a phenotype, which was not observed on overexpression of LTbeta alone. Reciprocal bone marrow transfers between LT-overexpressing and receptor-ablated mice show that involution was not due to a T cell-autonomous defect but was triggered by TNFR1 and LTbetaR signaling to radioresistant stromal cells. Thymic involution was partially prevented by the removal of one allele of LTbetaR but not of TNFR1, establishing a hierarchy in these signaling events. Infection with the lymphocytic choriomeningitis virus triggered a similar thymic pathology in wt, but not in Tnfr1(-/-) mice. These mice displayed elevated TNFalpha in both thymus and plasma, as well as increased LTs on both CD8(+) and CD4(-)CD8(-) thymocytes. These findings suggest that enhanced T cell-derived LT expression helps to control the physiological size of the thymic stroma and accelerates its involution via TNFR1/LTbetaR signaling in pathological conditions and possibly also in normal aging.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology

UniBE Contributor:

Macpherson, Andrew

ISSN:

0002-9440

ISBN:

18483211

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:05

Last Modified:

04 May 2014 23:20

Publisher DOI:

10.2353/ajpath.2008.070572

PubMed ID:

18483211

Web of Science ID:

000256326800013

URI:

https://boris.unibe.ch/id/eprint/28391 (FactScience: 120510)

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