Protein kinase C (PKC) alpha and PKC theta are the major PKC isotypes involved in TCR down-regulation

Marina von Essen, Martin W Nielsen, Charlotte M Bonefeld, Lasse Boding, Jeppe M Larsen, Michael Leitges, Gottfried Baier, Niels Odum, Carsten Geisler

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    Abstract

    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 PKCalpha and PKCtheta 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 Ser(126) and the di-leucine-based receptor-sorting motif of the CD3gamma chain. Finally, we found that PKCtheta was mainly implicated in down-regulation of directly engaged TCR, whereas PKCalpha was involved in down-regulation of nonengaged TCR.

    OriginalsprogEngelsk
    TidsskriftJournal of Immunology
    Vol/bind176
    Udgave nummer12
    Sider (fra-til)7502-10
    Antal sider9
    ISSN0022-1767
    DOI
    StatusUdgivet - 15 jun. 2006

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