title: Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5.
abstract: The loss of Gimap5 (GTPase of the immune-associated protein 5) gene function is the underlying cause of lymphopenia and autoimmune diabetes in the BioBreeding (BB) rat. The in vivo function of murine gimap5 is largely unknown. We show that selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells and compromises the survival of postthymic CD4 and CD8 cells, replicating findings in the BB rat model. In addition, gimap5 deficiency imposes a block of natural killer (NK)- and NKT-cell differentiation. Development of NK/NKT cells is restored on transfer of gimap5(-/-) bone marrow into a wild-type environment. Mice lacking gimap5 have a median survival of 15 weeks, exhibit chronic hepatic hematopoiesis, and in later stages show pronounced hepatocyte apoptosis, leading to liver failure. This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5(-/-) bone marrow into wild-type recipients. We conclude that mouse gimap5 is necessary for the survival of peripheral T cells, NK/NKT-cell development, and the maintenance of normal liver function. These functions involve cell-intrinsic as well as cell-extrinsic mechanisms.
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Schulteis
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chu
authors.forename: Xuezhi
authors.initials: X
authors.lastname: Dai
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Chen
authors.forename: Brandon
authors.initials: B
authors.lastname: Edwards
authors.forename: Dipica
authors.initials: D
authors.lastname: Haribhai
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Williams
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Malarkannan
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hessner
authors.forename: Sanja
authors.initials: S
authors.lastname: Glisic-Milosavljevic
authors.forename: Srikanta
authors.initials: S
authors.lastname: Jana
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kerschen
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
authors.forename: Demin
authors.initials: D
authors.lastname: Wang
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kwitek
authors.forename: Ake
authors.initials: A
authors.lastname: Lernmark
authors.forename: Jack
authors.initials: J
authors.lastname: Gorski
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival; D020558:GTP Phosphohydrolases / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D017093:Liver Failure / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D055611:Natural Killer T-Cells / Q000473:pathology*; D013601:T-Lymphocytes / Q000473:pathology*
chemical_list: C534135:Gimap5 protein, mouse; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins
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