Overexpression of Lymphotoxin in T Cells Induces Fulminant Thymic Involution

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 Tcell-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 (LT␤R), 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 LToverexpressing and receptor-ablated mice show that involution was not due to a T cell-autonomous defect but was triggered by TNFR1 and LT␤R signaling to radioresistant stromal cells. Thymic involution was partially prevented by the removal of one allele of LT␤R 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/ LT␤R signaling in pathological conditions and possibly also in normal aging.

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

“…Tg Lck-LTαβ mice develop a fulminant thymus involution that is dependent on LTα 3 /TNFR1 and LTα 1 β 2 /LTβR signaling within the cTEC recapitulating virus infection-related thymic involution by activated LTαβ-overexpressing T cells. 44,45 Therefore, to assess the role of NIK in cell death of cTEC, we performed bone marrow (BM) reconstitution assays using WT or Tg Lck-LTαβ mice as donors and WT or aly/aly NIK-deficient recipient mice. 46 For phenotypic analyses, 8 weeks postreconstitution mice were killed and thymi were imaged and quantitatively and qualitatively analyzed.…”

“…As previously reported, reconstitution of Lck-LTαβ BM into WT recipient mice led to a drastic reduction in thymus size compared with the reconstitution of WT BM into WT recipient mice (Figure 5a). 44 Reciprocal reconstitution experiments using Lck-LT αβ BM into aly/aly recipient mice greatly protected from LTαβ-induced thymus involution. Indeed, thymi were comparable in size to those obtained from reconstitution experiments of WT BM into WT recipient mice or aly/aly BM into aly/aly recipient mice.…”

“…Mice deficient for NIK (aly/aly) and NIK KO mice were provided by B Becher, (University of Zurich, Zurich, Switzerland) and p100/p52 (nfkb2 − / − ) mice were provided by J Caamano (University of Birmingham, Birmingham, UK), respectively, and Lck-LTαβ mice were previously described. 44 All mice were on a C57BL/6 genetic background and were bred and maintained under specific pathogen-free conditions and within protocols approved by the Institute of Virology, Technische Universität München (TUM)/ Helmholtz Zentrum München, Munich, Germany and the MRC Centre of Immune Regulation, University of Birmingham, Birmingham, UK. For control of lethal irradiation (1100 rad) and reconstitution efficiency, reconstitution into WT recipient mice was performed using BM derived from β-Actin Green Fluorescent Protein (β-Act GFP) transgenic mice and gave a reconstitution efficiency of 89-97% (data not shown).…”

“…Relative thymus weight, histology analysis, TUNEL staining and Annexin V/7-AAD staining were performed as previously described. 44 Pictures were taken with an Olympus BX53 microscope. Cell counting were performed with the 'CellSens Dimension' software from Olympus (Hamburg, Germany).…”

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…The role of LT in the context of lymphoid neogenesis, development of autoimmune diseases and inflammatory disorders was further investigated in vivo (Picarella et al, 1992;Kratz et al, 1996;Luther et al, 2000;Drayton et al, 2003Drayton et al, , 2006Gommerman and Browning, 2003;Martin et al, 2004;Heikenwalder et al, 2005Heikenwalder et al, , 2008Haybaeck et al, 2009). These studies revealed that ectopic LT expression suffices to generate lymphoid-like structures (Picarella et al, 1992;Kratz et al, 1996;Gommerman and Browning, 2003;Heikenwalder et al, 2005;Haybaeck et al, 2009), also termed tertiary lymphoid organs or tissues.…”