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Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5

Author:
  • Ryan D. Schulteis
  • Haiyan Chu
  • Xuezhi Dai
  • Yuhong Chen
  • Brandon Edwards
  • Dipica Haribhai
  • Calvin B. Williams
  • Subramaniam Malarkannan
  • Martin J Hessner
  • Sanja Glisic-Milosavljevic
  • Srikanta Jana
  • Edward J. Kerschen
  • Soumitra Ghosh
  • Demin Wang
  • Anne E. Kwitek
  • Ake Lernmark
  • Jack Gorski
  • Hartmut Weiler
Publishing year: 2008
Language: English
Pages: 4905-4914
Publication/Series: Blood
Volume: 112
Issue: 13
Document type: Journal article
Publisher: American Society of Hematology

Abstract english

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.

Other

Published
  • ISSN: 0006-4971
E-mail: ake [dot] lernmark [at] med [dot] lu [dot] se

Principal investigator

Diabetes and Celiac Unit

+46 40 39 19 01

+46 70 616 47 79

60:11:015

Jan Waldenströms gata 35, Malmö

33

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00