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CD28 Ligation Costimulates Cell Death but Not Maturation of Double-Positive Thymocytes due to Defective ERK MAPK Signaling¹

Daniel B. Graham^*, Michael P. Bell^*, Catherine J. Huntoon^*, Matthew D. Griffin, Xuguang Tai, Alfred Singer and David J. McKean^2,*

^* Department of Immunology and Department of Nephrology, Mayo Clinic College of Medicine, Rochester, MN 55905; and Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

The differentiation of double-positive (DP) CD4⁺CD8⁺ thymocytes to single-positive CD4⁺ or CD8⁺ T cells is regulated by signals that are initiated by coengagement of the Ag (TCR) and costimulatory receptors. CD28 costimulatory receptors, which augment differentiation and antiapoptotic responses in mature T lymphocytes, have been reported to stimulate both differentiation and apoptotic responses in TCR-activated DP thymocytes. We have used artificial APCs that express ligands for TCR and CD28 to show that CD28 signals increase expression of CD69, Bim, and cell death in TCR-activated DP thymocytes but do not costimulate DP thymocytes to initiate the differentiation program. The lack of a differentiation response is not due to defects in CD28-initiated TCR proximal signaling events but by a selective defect in the activation of ERK MAPK. To characterize signals needed to initiate the death response, a mutational analysis was performed on the CD28 cytoplasmic domain. Although mutation of all of CD28 cytoplasmic domain signaling motifs blocks cell death, the presence of any single motif is able to signal a death response. Thus, there is functional redundancy in the CD28 cytoplasmic domain signaling motifs that initiate the thymocyte death response. In contrast, immobilized Abs can initiate differentiation responses and cell death in DP thymocytes. However, because Ab-mediated differentiation occurs through CD28 receptors with no cytoplasmic domain, the response may be mediated by increased adhesion to immobilized anti-TCR Abs.

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 Mayo Foundation and National Institutes of Health (AI44959; to D.J.M.).

² Address correspondence and reprint requests to Dr. David J. McKean, Department of Immunology, Mayo Clinic, 301 Guggenheim Building, Rochester, MN 55905. E-mail address: mckean.david{at}mayo.edu

³ Abbreviations used in this paper: DP, double positive; SP, single positive; Treg, T regulatory; CHO, Chinese hamster ovary; PI, propidium iodide; WT, wild type; MFI, mean fluorescence intensity; PLC, phospholipase C; pERK, phosphorylated ERK; TR, truncated.

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