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Impaired NFAT Transcriptional Activity in Antigen-Stimulated CD8 T Cells Linked to Defective Phosphorylation of NFAT Transactivation Domain¹

Stéphane Leung-Theung-Long^2,*,, Isabelle Mondor^2,,,¶, Martine Guiraud^*,, Camille Lamare^*,, Viswas Nageleekar^||, Pierre-Emmanuel Paulet^*,, Mercedes Rincon^|| and Sylvie Guerder^3,*,,,,¶

^* Institut National de la Santé et de la Recherche Médicale, Unité 563 and Université Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Centre d’Immunologie de Marseille-Luminy, Université de la Méditerranée, Institut National de la Santé et de la Recherche Médicale, Unité 631, and ^¶ Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6102, Marseille, France; and ^|| Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405

NFAT transcription factors play critical roles in CD4 T cell activation and differentiation. Their function in CD8 T cell is, however, unknown. We show in this study that, in contrast to CD4 T cells, Ag-stimulated CD8 T cells do not demonstrate NFAT transcriptional activity despite normal regulation of NFAT nuclear shuttling. Further analysis of the signaling defect shows that phosphorylation of the ⁵³SSPS⁵⁶ motif of the NFAT transactivation domain is essential for NFAT-mediated transcription in primary T cells. Although Ag stimulation induces in CD4 T cells extensive phosphorylation of this motif, it does so only minimally in CD8 T cells. Although Ag stimulation triggers only modest activation of the p38 MAPK in CD8 T cells as opposed to CD4 T cells, p38 MAPK is not the upstream kinase that directly or indirectly phosphorylates the NFAT ⁵³SSPS⁵⁶ motif. These findings reveal an unsuspected difference between CD4 and CD8 T cells in the TCR downstream signaling pathway. Therefore, whereas in CD4 T cells TCR/CD28 engagement activates a yet unknown kinase that can phosphorylate the NFAT ⁵³SSPS⁵⁶ motif, this pathway is only minimally triggered in CD8 T cells, thus limiting NFAT transcriptional activity.

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 institutional grants to S.G. from Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique and by grants from Association pour la Recherche sur le Cancer and National Institutes of Health Grant R01-AI051454 (to M.R.). S.L.-T.-L. was supported by a fellowship from the Ligue Nationale Contre le Cancer.

² S.L.-T.-L. and I.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Sylvie Guerder, Institut National de la Santé et de la Recherche Médicale, Unité 563, Centre de Physiopathologie de Toulouse-Purpan, Centre Hospitalier de l’Université Purpan, Boîte Postale 3028, 31024 Toulouse Cedex 3, France. E-mail address: Sylvie.guerder{at}inserm.fr

⁴ Abbreviations used in this paper: PKC, protein kinase C; HA, hemagglutinin; NFAT-luc, NFAT-luciferase.