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 Blood, 15 December 2008, Vol. 112, No. 13, pp. 4905-4914.
Prepublished online as a Blood First Edition Paper on September 16, 2008; DOI 10.1182/blood-2008-03-146555.

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Submitted March 24, 2008
Accepted June 15, 2008

Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking gimap5

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, and Hartmut Weiler*

Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI, United States
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States
Department of Medicine, University of Washington, Seattle, WA, United States

* Corresponding author; email: hartmut.weiler{at}bcw.edu.

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 post-thymic CD4 and CD8 cells, replicating findings in the BB rat model. In addition, gimap5-deficiency imposes a block of NK and NKT cell differentiation. Development of NK/NKT cells is restored upon 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.


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