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

Activated lymphocytes and lymphoid-tissue inducer cells expresslymphotoxins (LTs), which are essential for the organogenesisand maintenance of lymphoreticular microenvironments. Here wedescribe that T-cell-restricted overexpression of LT inducesfulminant thymic involution. This phenotype was prevented byablation of the LT receptors tumor necrosis factor receptor(TNFR) 1 or LT beta receptor (LTβR), representing two non-redundantpathways. Multiple lines of transgenic Lt ${alpha}$ β and Lt ${alpha}$ miceshow such a phenotype, which was not observed on overexpressionof LTβ alone. Reciprocal bone marrow transfers betweenLT-overexpressing and receptor-ablated mice show that involutionwas not due to a T cell-autonomous defect but was triggeredby TNFR1 and LTβR signaling to radioresistant stromal cells.Thymic involution was partially prevented by the removal ofone allele of LTβR but not of TNFR1, establishing a hierarchyin these signaling events. Infection with the lymphocytic choriomeningitisvirus triggered a similar thymic pathology in wt, but not inTnfr1^–/– mice. These mice displayed elevated TNF ${alpha}$ in both thymus and plasma, as well as increased LTs on bothCD8⁺ and CD4^–CD8^– thymocytes. These findings suggestthat enhanced T cell-derived LT expression helps to controlthe physiological size of the thymic stroma and acceleratesits involution via TNFR1/LTβR signaling in pathologicalconditions and possibly also in normal aging.