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The Role of Diacylglycerol Kinases in T Cell Anergy

  • X. P. Zhong
  • B. A. Olenchock
  • G. A. Koretzky
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2007/3)

Abstract

Engagement of the T cell antigen receptor (TCR) results in the activation of multiple biochemical second messenger cascades that must be integrated for the appropriate T cell response. Once the critical TCR-stimulated signaling pathway is initiated by activation of protein tyrosine kinases, a series of adapter proteins is recruited that brings tyrosine-phosphorylated phospholipase Cγ1 into the vicinity of its substrate, phosphatidylinositol-4,5-bisphosphate, resulting in the formation of two second messengers, inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Previous work from multiple laboratories has shown that the balance between signals downstream of IP3 versus those downstream of DAG has profound effects on the fate of the stimulated T cells. In this report we summarize our recent data indicating that one key determinant of this balance of signals is the activity of members of the diacylglycerol kinase family, enzymes that convert DAG into phosphatidic acid.

Keywords

Jurkat Cell Phosphatidic Acid Wildtype Mouse Cell Anergy Cell Effector Function 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Dower NA, Stang SL, Bottorff DA, Ebinu JO, Dickie P, Ostergaard HL, Stone JC (2000) RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nat Immunol 1:317–321PubMedCrossRefGoogle Scholar
  2. Ebinu JO, Stang SL, Teixeira C, Bottorff DA, Hooton J, Blumberg PM, Barry M, Bleakley RC, Ostergaard HL, Stone JC (2000) RasGRP links T-cell receptor signaling to Ras. Blood 95:3199–3203PubMedGoogle Scholar
  3. Jenkins MK, Pardoll DM, Mizuguchi J, Chused TM, Schwartz RH (1987) Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc Natl Acad Sci USA 84:5409–5413PubMedCrossRefGoogle Scholar
  4. Jordan MS, Singer AL, Koretzky GA (2003) Adaptors as central mediators of signal transduction in immune cells. Nat Immunol 4:110–116PubMedCrossRefGoogle Scholar
  5. Kazanietz MG (2005) Targeting protein kinase C and “non-kinase” phorbol ester receptors: emerging concepts and therapeutic implications. Biochim Biophys Acta 1754:296–304PubMedGoogle Scholar
  6. Luo B, Regier DS, Prescott SM, Topham MK (2004) Diacylglycerol kinases. Cell Signal 16:983–989PubMedGoogle Scholar
  7. Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A (2002) Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109:719–731PubMedCrossRefGoogle Scholar
  8. Macian F, Im SH, Garcia-Cozar FJ, Rao A (2004) T-cell anergy. Curr Opin Immunol 16:209–216PubMedCrossRefGoogle Scholar
  9. Olenchock BA, Guo R, Carpenter JH, Jordan M, Topham MK, Koretzky GA, Zhong XP (2006) Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol 7:1174–1181PubMedCrossRefGoogle Scholar
  10. Sanjuán MA, Pradet-Balade B, Jones DR, Martínez-A C, Stone JC, Garcia-Sanz JA, Mérida I (2003) T cell activation in vivo targets diacylglycerol kinase α to the membrane: a novel mechanism for Ras attenuation. J Immunol 170:2877–2883PubMedGoogle Scholar
  11. Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334PubMedCrossRefGoogle Scholar
  12. van Blitterswijk WJ, Houssa B (2000) Properties and functions of diacylglycerol kinases. Cell Signal 12:595–605PubMedCrossRefGoogle Scholar
  13. Zhong XP, Hainey EA, Olenchock BA, Zhao H, Topham MK, Koretzky GA (2002) Regulation of T cell receptor-induced activation of the Ras-ERK pathway by diacylglycerol kinase zeta. J Biol Chem 277:31089–31098PubMedCrossRefGoogle Scholar
  14. Zhong XP, Hainey EA, Olenchock BA, Jordan MS, Maltzman JS, Nichols KE, Shen H, Koretzky GA (2003) Enhanced T cell responses due to diacylglycerol kinase zeta deficiency. Nat Immunol 4:882–890PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • X. P. Zhong
    • 1
  • B. A. Olenchock
    • 1
  • G. A. Koretzky
    • 1
  1. 1.Department of Pathology and Laboratory Medicine, Division of RheumatologyAbramson Family Cancer Research InstitutePhiladelphiaUSA

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