The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-kB and activate T cells

Sung-Gyoo Park, et al. 2009. Nat. Immunol. 10, 158-166

Student: Chia-Hui Huang (黃佳慧)                       Time: 14:00~15:00, May 20, 2009

Commentator: Dr. Pin Ling (凌斌老師)               Place: Room 601

Abstract:

        Full activation of T cells by antigen-presenting cells requires two stimulatory signals, one through the TCR-MHC complex and a second through a coreceptor such as CD28. Engagement of CD28 coreceptor by costimulatory molecule B7 is required for the activation of transcription factors NF-kB, NFAT and AP-1 [1], and allows for the production of IL-2 and cell proliferation. However, the distinct signaling cascade of TCR-CD28 to initiate the NF-kB activation pathway has remained incompletely understood. The 3-phosphoinositide-dependent protein kinase-1 (PDK1) is involved in a variety of cell functions, including protein synthesis, cell survival, cell metabolism, and cell adhesion and migration, so it can be expected that PDK1-knockout embryos die in early developmental stage [2]. In this study, the authors used a mouse model with T cell-specific deletion of PDK1 and found that PDK1 was required for CD4⁺ T cell activation in CD28 engagement, but not in other signaling pathways, such as those involving Jnk, p38 and NFAT. Unexpectedly, CD4⁺ T cell survival was unaffected, although PDK1 was reported to participate in cell survival and metabolism. CD28 ligation also regulated PDK1 localization and phosphorylation on Thr513. The phosphorylated PDK1 interacted with PKC-q and recruited CARMA1, thereby allowing PKC-q to phosphorylate CARMA1, which was essential for NF-kB activation. In conclusion, CD28-induced phosphorylation of PDK1 at Thr513 is important for PDK1 regulation during TCR-CD28 signaling, leading to NF-kB activation.

References:

1.      Rincon, M. & Flavell, R.A. 1994. AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes. EMBO J. 13, 4370–4381.

2.      Lawlor, M.A. et al. 2002. Essential role of PDK1 in regulating cell size and development in mice. EMBO J. 21, 3728–3738.