Impaired NFAT Transcriptional Activity in Antigen-Stimulated CD8 T Cells Linked to Defective Phosphorylation of NFAT Transactivation Domain
Impaired NFAT Transcriptional Activity in Antigen-Stimulated CD8 T Cells Linked to Defective Phosphorylation of NFAT Transactivation Domain
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DOI：
10.4049/jimmunol.0803539
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发表时间：
2009-06-01
影响因子：
4.4
通讯作者：
Guerder, Sylvie
中科院分区：
文献类型：
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作者：
Leung-Theung-Long, Stephane;Mondor, Isabelle;Guerder, Sylvie
NFAT转录因子在CD4 T细胞活化和分化中起关键作用。然而，它们在CD8 T细胞中的功能是未知的。我们在这项研究中表明，与CD4 T细胞相反，Ag刺激的CD8 T细胞不表现出NFAT转录活性，尽管NFAT核穿梭正常调节。对信号传导缺陷的进一步分析表明，NFAT反式激活结构域的（SSPS 56）-S-53基序的磷酸化对于原代T细胞中NFAT介导的转录是必需的。尽管Ag刺激在CD4 T细胞中诱导该基序的广泛磷酸化，但在CD8 T细胞中仅最低限度地诱导。虽然Ag刺激在CD8 T细胞中仅触发p38 MAPK的适度活化，而不是在CD4 T细胞中，但p38 MAPK不是直接或间接磷酸化NFAT（SSPS 56）-S-53基序的上游激酶。这些发现揭示了CD4和CD8 T细胞在TCR下游信号通路中的意料之外的差异。因此，尽管在CD4 T细胞中TCR/CD28接合激活了可以磷酸化NFAT（SSPS 56）-S-53基序的未知激酶，但该途径在CD8 T细胞中仅被最低限度地触发，从而限制了NFAT转录活性。免疫学杂志，2009，182：6807 - 6814.
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 (SSPS56)-S-53 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 (SSPS56)-S-53 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 (SSPS56)-S-53 motif, this pathway is only minimally triggered in CD8 T cells, thus limiting NFAT transcriptional activity. The Journal of Immunology, 2009, 182: 6807-6814.