Impaired NFAT transcriptional activity in antigen-stimulated CD8 T cells linked to defective phosphorylation of NFAT transactivation domain.
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 (53)SSPS(56) 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 (53)SSPS(56) 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 (53)SSPS(56) motif, this pathway is only minimally triggered in CD8 T cells, thus limiting NFAT transcriptional activity.
Leung-Theung-Long
Stéphane
S
Institut Unité 563, Institut National de la Santé et de la Recherche Médicale, Université Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Mondor
Isabelle
I
Guiraud
Martine
M
Lamare
Camille
C
Nagaleekar
Viswas
V
Nageleekar
Viswas
V
Paulet
Pierre-Emmanuel
PE
Rincon
Mercedes
M
Guerder
Sylvie
S
D021581:Active Transport, Cell Nucleus; D020816:Amino Acid Motifs; D000818:Animals; D000941:Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D015533:Transcriptional Activation
D000941:Antigens; D050778:NFATC Transcription Factors