1. Accelerated thymic atrophy as a result of elevated homeostatic expression of the genes encoded by the TNF/lymphotoxin cytokine locus
- Author
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Marina S. Drutskaya, Andrei A. Kruglov, Shakhov An, Sergei A. Nedospasov, Arthur R. Galimov, Lionel Feigenbaum, Alexei V. Tumanov, Anna Kuchmiy, Dmitry V. Kuprash, Sergei I. Grivennikov, Yuriy V. Shebzukhov, and Dmitry J. Liepinsh
- Subjects
Lymphotoxin alpha ,Lymphotoxin-beta ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,Double negative ,Gene Dosage ,Gene Expression ,Apoptosis ,Cell Count ,Mice, Transgenic ,Thymus Gland ,Biology ,Major histocompatibility complex ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Lymphotoxin beta Receptor ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Animals ,Humans ,Receptor ,Lymphotoxin-alpha ,030304 developmental biology ,Bone Marrow Transplantation ,Cell Proliferation ,Mice, Knockout ,0303 health sciences ,Tumor Necrosis Factor-alpha ,Keratin-8 ,Stem Cells ,Epithelial Cells ,3. Good health ,Mice, Inbred C57BL ,Cytokine ,Lymphotoxin ,Receptors, Tumor Necrosis Factor, Type I ,biology.protein ,Tumor necrosis factor alpha ,Atrophy ,030215 immunology - Abstract
TNF, lymphotoxin (LT)-alpha, LT-beta and LIGHT are members of a larger superfamily of TNF-related cytokines that can cross-utilize several receptors. Although LIGHT has been implicated in thymic development and function, the role of TNF and LT remains incompletely defined. To address this, we created a model of modest homeostatic overexpression of TNF/LT cytokines using the genomic human TNF/LT locus as a low copy number Tg. Strikingly, expression of Tg TNF/LT gene products led to profound early thymic atrophy characterized by decreased numbers of thymocytes and cortical thymic epithelial cells, partial block of thymocyte proliferation at double negative (DN) 1 stage, increased apoptosis of DN2 thymocytes and severe decline of T-cell numbers in the periphery. Results of backcrossing to TNFR1-, LTbetaR- or TNF/LT-deficient backgrounds and of reciprocal bone marrow transfers implicated both LT-alpha/LT-beta to LTbetaR and TNF/LT-alpha to TNFR1 signaling in accelerated thymus degeneration. We hypothesize that chronic infections can promote thymic atrophy by upregulating LT and TNF production.
- Published
- 2009