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The Essential Role of LAT in Thymocyte Development during Transition from the Double-Positive to Single-Positive Stage¹

Department of Immunology, Duke University Medical Center, Durham, NC 27710

The linker for activation of T cells (LAT) is an adaptor protein that couples TCR engagement to downstream signaling cascades. LAT is important in early thymocyte development as LAT-deficient mice have a complete block at the double-negative (DN) 3 stage. To study the role of LAT beyond the DN3 stage, we generated mice in which the lat gene could be deleted by the Cre recombinase. Analysis of these mice showed that deletion of LAT after the DN3 stage allowed thymocytes to develop past the DN3 to DN4 checkpoint and to generate double-positive thymocytes. However, LAT-deficient DP thymocytes were severely defective in responding to stimulation via the TCR and failed to differentiate into single-positive thymocytes efficiently. Consequently, few LAT-deficient mature T cells could be found in the periphery. These T cells had undergone extensive homeostatic proliferation and expressed low levels of the TCR on their surface. Collectively, our data indicate that in addition to its role in pre-TCR signaling, LAT also plays an essential role in thymocyte development during transition from the double-positive to single-positive stage.

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¹ This work was supported by National Institutes of Heath Grants AI048674 and AI056156. W.Z. is a scholar of Leukemia and Lymphoma Society. J.L. is supported by a National Science Scholarship from A*STAR, Singapore.

² Address correspondence and reprint requests to Dr. Weiguo Zhang, Department of Immunology, Duke University Medical Center, Box 3010, Durham, NC 27710. E-mail address: zhang033{at}mc.duke.edu

³ Abbreviations used in this paper: LAT, linker for activation of T cells; DN, double negative; DP, double positive; ISP, immature single positive; SP, single positive; Treg cell, regulatory T cell.