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Protein Kinase C- Is Required for Efficient Positive Selection¹

Sharon Celeste Morley^*,, K. Scott Weber, Henry Kao and Paul M. Allen^2,

^* Department of Pediatrics, Division of Pediatric Infectious Diseases, and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

Protein kinase C- (PKC) is critical for TCR-initiated signaling in mature T cells, but initial reports found no requirement for PKC in thymocyte development. Thymocytes and peripheral T cells utilize many of the same signaling components and, given the significant role of PKC in peripheral T cells, it was surprising that it was not involved at all in TCR signaling in thymocytes. We decided to re-evaluate the role of PKC in thymocyte development using the well-characterized class II-restricted n3.L2 TCR-transgenic TCR model. Analysis of n3.L2 PKC^–/– mice revealed a defect in thymocyte-positive selection, resulting in a 50% reduction in the generation of n3.L2 CD4 single-positive thymocytes and n3.L2 CD4 mature T cells. Competition between n3.L2 WT and n3.L2 PKC^–/– thymocytes in bone marrow chimeras revealed a more dramatic defect, with a >80% reduction in generation of n3.L2 CD4 single-positive thymocytes derived from PKC^–/– mice. Inefficient positive selection of n3.L2 PKC^–/– CD4 single-positive cells resulted from "weaker" signaling through the TCR and correlated with diminished ERK activation. The defect in positive selection was not complete in the PKC^–/– mice, most likely accounted for by compensation by other PKC isoforms not evident in peripheral cells. Similar decreased positive selection of both CD4 and CD8 single-positive thymocytes was also seen in nontransgenic PKC^–/– mice. These findings now place PKC as a key signaling molecule in the positive selection of thymocytes as well as in the activation of mature T cells.

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 the Pediatric Infectious Diseases Society-St. Jude Fellowship Award for Basic Research (to S.C.M.). P.M.A. is supported by grants from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Paul M. Allen, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8118, St. Louis, MO 63110. E-mail address: pallen{at}wustl.edu

³ Abbreviations used in this paper: PKC, protein kinase C; Cab, clonotypic Ab; APL, altered peptide ligand; pI-E^k, I-E^k with the antigenic peptide; DP, double positive; SP, single positive; MFI, mean fluorescence intensity; AICD, activation-induced cell death; Treg, regulatory T; WT, wild type; DN, double negative; pMHC, peptide-MHC.