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The Effector Functions of Mature T Lymphocytes Are Impaired in Transgenic Mice Expressing the SH2 Domain of TSAd/Lad

  • Choi, Youngbong (Department of Life Science, Ewha Womans University) ;
  • Park, Eunkyung (Department of Life Science, Ewha Womans University) ;
  • Ahn, Eunseon (Department of Life Science, Ewha Womans University) ;
  • Park, Inyoung (Department of Life Science, Ewha Womans University) ;
  • Yun, Yungdae (Department of Life Science, Ewha Womans University)
  • Received : 2009.04.21
  • Accepted : 2009.07.27
  • Published : 2009.09.30

Abstract

TSAd/Lad is a T cell adaptor molecule involved in $p56^{lck}$-mediated T cell activation. To investigate the functions of TSAd in T cells, we generated transgenic (TG) mice expressing the SH2 domain of TSAd (TSAd-SH2) under the control of the $p56^{lck}$ proximal promoter. In T cells from TSAd-SH2 TG mice, T cell receptor (TCR)-mediated early signaling events, such as $Ca^{2+}$ flux and ERK activation, were normal; however, late activation events, such as IL-2 production and proliferation, were significantly reduced. Moreover, TCR-induced cell adhesion to extracellular matrix (ECM) proteins and migration through ECM proteins were defective in T cells from TSAd-SH2 TG mice. Furthermore, the contact hypersensitivity (CHS) reaction, an inflammatory response mainly mediated by T helper 1 (Th1) cells, was inhibited in TSAd-SH2 TG mice. Taken together, these results show that TSAd, particularly the SH2 domain of TSAd, is essential for the effector functions of T cells.

Keywords

Acknowledgement

Supported by : Center for Cell Signaling and Drug Discovery, Ewha Womans University

References

  1. Ben-Horin, S., and Bank, I. (2004). The role of very late antigen-1 in immune-mediated inflammation. Clin. Immunol. 113, 119-129 https://doi.org/10.1016/j.clim.2004.06.007
  2. Burbach, B.J., Medeiros, R.B., Mueller, K.L., and Shimizu, Y. (2007). T-cell receptor signaling to integrins. Immunol. Rev. 218, 65-81 https://doi.org/10.1111/j.1600-065X.2007.00527.x
  3. Cavani, A., Albanesi, C., Traidl, C., Sebastiani, S., and Girolomoni, G. (2001). Effector and regulatory T cells in allergic contact dermatitis. Trends Immunol. 22, 118-120 https://doi.org/10.1016/S1471-4906(00)01815-9
  4. Chaffin, K.E., Beals, C.R., Wilkie, T.M., Forbush, K.A., Simon, M.I., and Perlmutter, R.M. (1990). Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADPribosyltransferase. EMBO J. 9, 3821-3829
  5. Choi, Y.B., Kim, C.K., and Yun, Y. (1999). Lad, an adapter protein interacting with the SH2 domain of p56lck, is required for T cell activation. J. Immunol. 163, 5242-5249
  6. Dai, R.M., and Li, C.C. (2001). Valosin-containing protein is a multiubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nat. Cell Biol. 3, 740-744 https://doi.org/10.1038/35087056
  7. Grabbe, S., and Schwarz, T. (1998). Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19, 37-44 https://doi.org/10.1016/S0167-5699(97)01186-9
  8. Granum, S., Andersen, T. C., Sorlie, M., Jorgensen, M., Koll, L., Berge, T., Lea, T., Fleckenstein, B., Spurkland, A., and Sundvold- Gjerstad, V. (2008). Modulation of Lck function through multisite docking to T cell-specific adapter protein. J. Biol. Chem. 283, 21909-21919 https://doi.org/10.1074/jbc.M800871200
  9. Jang, M., Park, B.C., Kang, S., Lee do, H., Cho, S., Lee, S.C., Bae, K.H., and Park, S.G. (2008). Mining of caspase-7 substrates using a degradomic approach. Mol. Cells 26, 152-157
  10. Kliche, S., Breitling, D., Togni, M., Pusch, R., Heuer, K., Wang, X., Freund, C., Kasirer-Friede, A., Menasche, G., Koretzky, G.A., et al. (2006). The ADAP/SKAP55 signaling module regulates T-cell receptor-mediated integrin activation through plasma membrane targeting of Rap1. Mol. Cell. Biol. 26, 7130-7144 https://doi.org/10.1128/MCB.00331-06
  11. Lanzavecchia, A., and Sallusto, F. (2001). Antigen decoding by T lymphocytes: from synapses to fate determination. Nat. Immunol. 2, 487-492 https://doi.org/10.1038/88678
  12. Leo, A., and Schraven, B. (2001). Adapters in lymphocyte signalling. Curr. Opin. Immunol. 13, 307-316 https://doi.org/10.1016/S0952-7915(00)00220-X
  13. Madeo, F., Schlauer, J., Zischka, H., Mecke, D., and Frohlich, K.U. (1998). Tyrosine phosphorylation regulates cell cycle-dependent nuclear localization of Cdc48p. Mol. Biol. Cell 9, 131-141 https://doi.org/10.1091/mbc.9.1.131
  14. Marti, F., and King, P.D. (2005). The p95-100 kDa ligand of the T cell-specific adaptor (TSAd) protein Src-homology-2 (SH2) domain implicated in TSAd nuclear import is p97 Valosincontaining protein (VCP). Immunol. Lett. 97, 235-243 https://doi.org/10.1016/j.imlet.2004.10.021
  15. Marti, F., Post, N.H., Chan, E., and King, P.D. (2001). A transcription function for the T cell-specific adapter (TSAd) protein in T cells: critical role of the TSAd Src homology 2 domain. J. Exp. Med. 193, 1425-1430 https://doi.org/10.1084/jem.193.12.1425
  16. Marti, F., Garcia, G.G., Lapinski, P.E., MacGregor, J.N., and King, P.D. (2006). Essential role of the T cell-specific adapter protein in the activation of LCK in peripheral T cells. J. Exp. Med. 203, 281-287 https://doi.org/10.1084/jem.20051637
  17. Mustelin, T., and Tasken, K. (2003). Positive and negative regulation of T-cell activation through kinases and phosphatases. Biochem. J. 371, 15-27 https://doi.org/10.1042/BJ20021637
  18. Park, D., Park, I., Lee, D., Choi, Y.B., Lee, H., and Yun, Y. (2007). The adaptor protein Lad associates with the G protein beta subunit and mediates chemokine-dependent T-cell migration. Blood 109, 5122-5128 https://doi.org/10.1182/blood-2005-10-061838
  19. Pribila, J.T., and Shimizu, Y. (2003). Signal transduction events regulating integrin function and T cell migration: new functions and complexity. Immunol. Res. 27, 107-128 https://doi.org/10.1385/IR:27:1:107
  20. Rajagopal, K., Sommers, C.L., Decker, D.C., Mitchell, E.O., Korthauer, U., Sperling, A.I., Kozak, C.A., Love, P.E., and Bluestone, J.A. (1999). RIBP, a novel Rlk/Txk- and itk-binding adaptor protein that regulates T cell activation. J. Exp. Med. 190, 1657-1668 https://doi.org/10.1084/jem.190.11.1657
  21. Shimizu, C., Kawamoto, H., Yamashita, M., Kimura, M., Kondou, E., Kaneko, Y., Okada, S., Tokuhisa, T., Yokoyama, M., Taniguchi, M.I et al. (2001). Progression of T cell lineage restriction in the earliest subpopulation of murine adult thymus visualized by the expression of lck proximal promoter activity. Int. Immunol. 13, 105-117 https://doi.org/10.1093/intimm/13.1.105
  22. Spurkland, A., Brinchmann, J.E., Markussen, G., Pedeutour, F., Munthe, E., Lea, T., Vartdal, F., and Aasheim, H.C. (1998). Molecular cloning of a T cell-specific adapter protein (TSAd) containing an Src homology (SH) 2 domain and putative SH3 and phosphotyrosine binding sites. J. Biol. Chem. 273, 4539-4546 https://doi.org/10.1074/jbc.273.8.4539
  23. Vandermoere, F., El Yazidi-Belkoura, I., Slomianny, C., Demont, Y., Bidaux, G., Adriaenssens, E., Lemoine, J., and Hondermarck, H. (2006). The valosin-containing protein (VCP) is a target of Akt signaling required for cell survival. J. Biol. Chem. 281, 14307-14313 https://doi.org/10.1074/jbc.M510003200
  24. Weninger, W., Crowley, M.A., Manjunath, N., and von Andrian, U.H. (2001). Migratory properties of naive, effector, and memory CD8(+) T cells. J. Exp. Med. 194, 953-966 https://doi.org/10.1084/jem.194.7.953
  25. Xu, H., DiIulio, N.A., and Fairchild, R.L. (1996). T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: interferon gamma-producing (Tc1) effector CD8+ T cells and interleukin (Il) 4/Il-10-producing (Th2) negative regulatory CD4+ T cells. J. Exp. Med. 183, 1001-1012 https://doi.org/10.1084/jem.183.3.1001

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