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Selective Regulation of TCR Signaling Pathways by the CD45 Protein Tyrosine Phosphatase during Thymocyte Development¹

Rustom Falahati^* and David Leitenberg^2,*,

^* Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC 20037; and Children’s National Medical Center, Washington, DC 20010

In CD45-deficient animals, there is a severe defect in thymocyte-positive selection, resulting in an absence of mature T cells and the accumulation of thymocytes at the DP stage of development. However, the signaling defect(s) responsible for the block in development of mature single-positive T cells is not well characterized. Previous studies have found that early signal transduction events in CD45-deficient cell lines and thymocytes are markedly diminished following stimulation with anti-CD3. Nevertheless, there are also situations in which T cell activation and TCR signaling events can be induced in the absence of CD45. For example, CD45-independent TCR signaling can be recovered upon simultaneous Ab cross-linking of CD3 and CD4 compared with cross-linking of CD3 alone. These data suggest that CD45 may differentially regulate TCR signaling events depending on the nature of the signal and/or on the differentiation state of the cell. In the current study, we have assessed the role of CD45 in regulating primary thymocyte activation following physiologic stimulation with peptide. Unlike CD3-mediated stimulation, peptide stimulation of CD45-deficient thymocytes induces diminished, but readily detectable TCR-mediated signaling events, such as phosphorylation of TCR-associated , ZAP70, linker for activation of T cells, and Akt, and increased intracellular calcium concentration. In contrast, phosphorylation of ERK, which is essential for positive selection, is more severely affected in the absence of CD45. These data suggest that CD45 has a selective role in regulating different aspects of T cell activation.

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 in part by grants from the Arthritis Foundation and American Cancer Society, and National Institutes of Health Grant AI42963 (to D.L.). This manuscript was prepared in partial fulfillment of the requirements for a Ph.D. degree in Institute for Biomedical Sciences, George Washington University (R.F.).

² Address correspondence and reprint requests to Dr. David Leitenberg, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, 2300 I Street, NW, Washington, DC 20037. E-mail address: dleit{at}gwu.edu

³ Abbreviations used in this paper: DP, double positive; LAT, linker for activation of T cells; pERK, phosphorylated ERK; PLC, phospholipase C; pMCC, moth cytochrome c peptide.