Accelerated thymic atrophy as a result of elevated homeostatic expression of the genes encoded by the TNF/lymphotoxin cytokine locus.
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.
Liepinsh
Dmitry J
DJ
Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia.
Kruglov
Andrei A
AA
Galimov
Arthur R
AR
Shakhov
Alexander N
AN
Shebzukhov
Yuriy V
YV
Kuchmiy
Anna A
AA
Grivennikov
Sergei I
SI
Tumanov
Alexei V
AV
Drutskaya
Marina S
MS
Feigenbaum
Lionel
L
Kuprash
Dmitry V
DV
Nedospasov
Sergei A
SA
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001284:Atrophy / Q000235:genetics* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002452:Cell Count; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000473:pathology; D018628:Gene Dosage / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D053533:Keratin-8 / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000378:metabolism; D053308:Lymphotoxin-beta / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D013234:Stem Cells / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D053533:Keratin-8; C486595:Krt8 protein, mouse; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha