Published online before print May 15, 2008

This Article Full Text (Rapid PDF) Supplemental Material All Versions of this Article: ajpath.2008.070572v1 172/6/1555    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Heikenwalder, M. Articles by Aguzzi, A. Search for Related Content PubMed PubMed Citation Articles by Heikenwalder, M. Articles by Aguzzi, A.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070572

Accepted for publication February 14, 2008.

Article

Overexpression of Lymphotoxin in T Cells Induces Fulminant Thymic Involution

Mathias Heikenwalder^*, Marco Prinz^*, Nicolas Zeller^*, Karl S. Lang, Tobias Junt, Simona Rossi^¶, Alexei Tumanov, Hauke Schmidt, Josef Priller^||, Lukas Flatz, Thomas Rülicke^**, Andrew J. Macpherson, Georg A. Holländer^¶, Sergei A. Nedospasov, and Adriano Aguzzi^*@

From the Institutes of Neuropathology,* and Experimental Immunology, University Hospital of Zürich, Zürich, Switzerland; the Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, and the Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia; the Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Pediatric Immunology,^¶ Department of Biomedicine, University of Basel, Basel, Switzerland; the Institute of Neuropathology and Neuropsychiatry,^|| Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany, the Institute of Laboratory Animal Science and Research Center Biomodels Austria,** University of Veterinary Medicine, Vienna, Austria; and the Institute for Neuropathology, the Georg-August-University, Göttingen, Germany

^@ To whom correspondence should be addressed. E-mail: adriano.aguzzi{at}usz.ch.

	Abstract

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 (LTR), representing two non-redundant pathways. Multiple lines of transgenic Lt and Lt mice show such a phenotype, which was not observed on overexpression of LT 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 LTR signaling to radioresistant stromal cells. Thymic involution was partially prevented by the removal of one allele of LTR 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 TNF 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/LTR signaling in pathological conditions and possibly also in normal aging.