title: c-Met signalling is required for efficient postnatal thymic regeneration and repair.
abstract: We have reported that in vivo administration of the hybrid cytokine rIL-7/HGFβ or rIL-7/HGFα, which contains interleukin-7 (IL-7) and the β- or α-chain of hepatocyte growth factor (HGF), significantly enhances thymopoiesis in mice after bone marrow transplantation. We have shown that the HGF receptor, c-Met, is involved in the effect of the hybrid cytokines. To address the role of c-Met signalling in thymocyte development and recovery, we generated conditional knockout (cKO) mice in which c-Met was specifically deleted in T cells by crossing c-Met(ft/ft) mice with CD4-Cre transgenic mice. We show here that although the number of total thymocytes and thymocyte subsets in young c-Met cKO mice is comparable to age-matched control (Ctrl) mice, the cKO mice were more susceptible to sub-lethal irradiation and dexamethasone treatment. This was demonstrated by low recovery in thymic cellularity in c-Met cKO mice after insult. Furthermore, the number of total thymocytes and thymocyte subsets was markedly reduced in 6- to 12-month-old cKO mice compared with age-matched Ctrl mice, and the thymic architecture of 12-month-old cKO mice was similar to that of 20-month-old wild-type mice. In addition, c-Met deficiency reduced cell survival and the expression of Bcl-xL in double-positive thymocytes, and decreased cell proliferation and the expression of cyclin E and cyclin-dependent kinase 5 in single-positive thymocytes. Our data indicate that c-Met signalling plays an important role in thymic regeneration after thymic insult. In addition, T-cell-specific inactivation of c-Met accelerates age-related thymic involution.
authors: Department of Allied Health Sciences, University of Connecticut, Storrs, CT, USA.
authors: Yinhong
authors: Y
authors: Song
authors: Min
authors: M
authors: Su
authors: Pranau
authors: P
authors: Panchatsharam
authors: Debra
authors: D
authors: Rood
authors: Laijun
authors: L
authors: Lai
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002470:Cell Survival; D019927:Cyclin E / Q000096:biosynthesis; D051360:Cyclin-Dependent Kinase 5 / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000276:immunology*; D012038:Regeneration / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D060168:Thymocytes / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D000893:Anti-Inflammatory Agents; C494812:Bcl2l1 protein, mouse; D019927:Cyclin E; D051020:bcl-X Protein; D003907:Dexamethasone; D019859:Proto-Oncogene Proteins c-met; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse
keywords: T cells; c-Met; regeneration; thymus