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Defective T Cell Development and Function in the Absence of Abelson Kinases¹

Jing Jin Gu^*, Nu Zhang, You-Wen He, Anthony J. Koleske and Ann Marie Pendergast^2,*

^* Department of Pharmacology and Cancer Biology, and Department of Immunology, Duke University Medical Center, Durham, NC 27710; and Department of Molecular Biophysics and Biochemistry, and Department of Neurobiology, Yale University, New Haven, CT 06520

Thymocyte proliferation, survival, and differentiation are tightly controlled by signaling from the pre-TCR. In this study, we show for the first time that the Abelson (Abl) kinases regulate proximal signaling downstream of the pre-TCR. Conditional deletion of Abl kinases in thymocytes reveals a cell-autonomous role for these proteins in T cell development. The conditional knockout mice have reduced numbers of thymocytes, exhibit an increase in the percentage of the CD4^–CD8^– double-negative population, and are partially blocked in the transition to the CD4⁺CD8⁺ double-positive stage. Moreover, the total number of T cells is greatly reduced in the Abl mutant mice, and the null T cells exhibit impaired TCR-induced signaling, proliferation, and cytokine production. Notably, Abl mutant mice are compromised in their ability to produce IFN-positive CD8 T cells and exhibit impaired CD8⁺ T cell expansion in vivo upon Listeria monocytogenes infection. Furthermore, Ab production in response to T cell-dependent Ag is severely impaired in the Abl mutant mice. Together these findings reveal cell-autonomous roles for the Abl family kinases in both T cell development and mature T cell function, and show that loss of these kinases specifically in T cells results in compromised immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI056266 (to A.M.P.) and CA92123 (to Y.-W.H.), and National Institute of Neurological Disorders and Stroke Grant NS39475 (to A.J.K.).

² Address correspondence and reprint requests to Dr. Ann Marie Pendergast, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710. E-mail address: pende014{at}mc.duke.edu

³ Abbreviations used in this paper: DN, double negative; Abl, Abelson; DP, double positive; LAT, linker for activation of T cells; NP, nitrophenylacetyl; PI, propidium iodide; PLC, phospholipase C; SP, single positive.

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