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Protein Kinase C (PKC) and PKC Are the Major PKC Isotypes Involved in TCR Down-Regulation¹

Marina von Essen^*, Martin W. Nielsen^*, Charlotte M. Bonefeld^*, Lasse Boding^*, Jeppe M. Larsen^*, Michael Leitges, Gottfried Baier, Niels Ødum^* and Carsten Geisler^2,*

^* Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark; Medical University, Hanover, Germany; and Department for Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria

It is well known that protein kinase C (PKC) plays an important role in regulation of TCR cell surface expression levels. However, eight different PKC isotypes are present in T cells, and to date the particular isotype(s) involved in TCR down-regulation remains to be identified. The aim of this study was to identify the PKC isotype(s) involved in TCR down-regulation and to elucidate the mechanism by which they induce TCR down-regulation. To accomplish this, we studied TCR down-regulation in the human T cell line Jurkat, in primary human T cells, or in the mouse T cell line DO11.10 in which we either overexpressed constitutive active or dominant-negative forms of various PKC isotypes. In addition, we studied TCR down-regulation in PKC knockout mice and by using small interfering RNA-mediated knockdown of specific PKC isotypes. We found that PKC and PKC were the only PKC isotypes able to induce significant TCR down-regulation. Both isotypes mediated TCR down-regulation via the TCR recycling pathway that strictly depends on Ser¹²⁶ and the di-leucine-based receptor-sorting motif of the CD3 chain. Finally, we found that PKC was mainly implicated in down-regulation of directly engaged TCR, whereas PKC was involved in down-regulation of nonengaged TCR.

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The JI 2006 176: 7141-7142. [Full Text]  

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