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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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HEMATOPOIESIS AND STEM CELLS

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

Ryan D. Schulteis1,2, Haiyan Chu1, Xuezhi Dai1, Yuhong Chen1, Brandon Edwards3, Dipica Haribhai3, Calvin B. Williams3, Subramaniam Malarkannan1, Martin J. Hessner3, Sanja Glisic-Milosavljevic3, Srikanta Jana3, Edward J. Kerschen1, Soumitra Ghosh3, Demin Wang1, Anne E. Kwitek2, Ake Lernmark4, Jack Gorski1, and Hartmut Weiler1,2

1 Blood Research Institute, Blood Center of Wisconsin, Milwaukee; Departments of 2 Physiology and 3 Pediatrics, Medical College of Wisconsin, Milwaukee; and 4 Department of Medicine, University of Washington, Seattle

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.


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