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http://dx.doi.org/10.14348/molcells.2020.0124

The Transmembrane Adaptor Protein LIME Is Essential for Chemokine-Mediated Migration of Effector T Cells to Inflammatiory Sites  

Park, Inyoung (Research Center for Cellular Homeostasis, Ewha Womans University)
Son, Myongsun (Department of Life Science, Ewha Womans University)
Ahn, Eunseon (Department of Life Science, Ewha Womans University)
Kim, Young-Woong (School of Biological Sciences, Seoul National University)
Kong, Young-Yun (School of Biological Sciences, Seoul National University)
Yun, Yungdae (Research Center for Cellular Homeostasis, Ewha Womans University)
Publication Information
Molecules and Cells / v.43, no.11, 2020 , pp. 921-934 More about this Journal
Abstract
Lck-interacting transmembrane adaptor 1 (LIME) has been previously identified as a raft-associated transmembrane protein expressed predominantly in T and B lymphocytes. Although LIME is shown to transduce the immunoreceptor signaling and immunological synapse formation via its tyrosine phosphorylation by Lck, a Src-family kinase, the in vivo function of LIME has remained elusive in the previous studies. Here we report that LIME is preferentially expressed in effector T cells and mediates chemokine-mediated T cell migration. Interestingly, in LIME-/- mice, while T cell receptor stimulation-dependent proliferation, differentiation to effector T cells, cytotoxic T lymphocyte (CTL) function and regulatory T lymphocyte (Treg) function were normal, only T cell-mediated inflammatory response was significantly defective. The reduced inflammation was accompanied by the impaired infiltration of leukocytes and T cells to the inflammatory sites of LIME-/- mice. More specifically, the absence of LIME in effector T cells resulted in the reduced migration and defective morphological polarization in response to inflammatory chemokines such as CCL5 and CXCL10. Consistently, LIME-/- effector T cells were found to be defective in chemokine-mediated activation of Rac1 and Rap1, and dysregulated phosphorylation of Pyk2 and Cas. Taken together, the present findings show that LIME is a critical regulator of inflammatory chemokine-mediated signaling and the subsequent migration of effector T cells to inflammatory sites.
Keywords
chemokine; effector T cells; Lck-interacting transmembrane adaptor 1; migration;
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1 Zhang, W., Trible, R.P., Zhu, M., Liu, S.K., McGlade, C.J., and Samelson, L.E. (2000). Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling. J. Biol. Chem. 275, 23355-23361.   DOI
2 Zhu, M., Janssen, E., Leung, K., and Zhang, W. (2002). Molecular cloning of a novel gene encoding a membrane-associated adaptor protein (LAX) in lymphocyte signaling. J. Biol. Chem. 277, 46151-46158.   DOI
3 Ahn, E., Lee, H., and Yun, Y. (2006). LIME acts as a transmembrane adapter mediating BCR-dependent B-cell activation. Blood 107, 1521-1527.   DOI
4 Cher, D.J. and Mosmann, T.R. (1987). Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J. Immunol. 138, 3688-3694.
5 Bonecchi, R., Bianchi, G., Bordignon, P.P., D'Ambrosio, D., Lang, R., Borsatti, A., Sozzani, S., Allavena, P., Gray, P.A., Mantovani, A., et al. (1998). Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med. 187, 129-134.   DOI
6 Brdicka, T., Cerny, J., and Horejsi, V. (1998). T cell receptor signalling results in rapid tyrosine phosphorylation of the linker protein LAT present in detergent-resistant membrane microdomains. Biochem. Biophys. Res. Commun. 248, 356-360.   DOI
7 Brdickova, N., Brdicka, T., Angelisova, P., Horvath, O., Spicka, J., Hilgert, I., Paces, J., Simeoni, L., Kliche, S., Merten, C., et al. (2003). LIME: a new membrane Raft-associated adaptor protein involved in CD4 and CD8 coreceptor signaling. J. Exp. Med. 198, 1453-1462.   DOI
8 Coates, T.D., Watts, R.G., Hartman, R., and Howard, T.H. (1992). Relationship of F-actin distribution to development of polar shape in human polymorphonuclear neutrophils. J. Cell Biol. 117, 765-774.   DOI
9 Dar, W.A. and Knechtle, S.J. (2007). CXCR3-mediated T-cell chemotaxis involves ZAP-70 and is regulated by signalling through the T-cell receptor. Immunology 120, 467-485.   DOI
10 Dikic, I., Dikic, I., and Schlessinger, J. (1998). Identification of a new Pyk2 isoform implicated in chemokine and antigen receptor signaling. J. Biol. Chem. 273, 14301-14308.   DOI
11 Fagerholm, S., Hilden, T.J., and Gahmberg, C.G. (2002). Lck tyrosine kinase is important for activation of the CD11a/CD18-integrins in human T lymphocytes. Eur. J. Immunol. 32, 1670-1678.   DOI
12 Goebeler, M., Trautmann, A., Voss, A., Brocker, E.V., Toksoy, A., and Gillitzer, R. (2001). Differential and sequential expression of multiple chemokines during elicitation of allergic contact hypersensitivity. Am. J. Pathol. 158, 431-440.   DOI
13 Fang, Y., Yu, S., Ellis, J.S., Sharav, T., and Braley-Mullen, H. (2010). Comparison of sensitivity of Th1, Th2, and Th17 cells to Fas-mediated apoptosis. J. Leukoc. Biol. 87, 1019-1028.   DOI
14 Finco, T.S., Kadlecek, T., Zhang, W., Samelson, L.E., and Weiss, A. (1998). LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway. Immunity 9, 617-626.   DOI
15 Garcia-Bernal, D., Wright, N., Sotillo-Mallo, E., Nombela-Arrieta, C., Stein, J.V., Bustelo, X.R., and Teixido, J. (2005). Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin alpha4beta1. Mol. Biol. Cell 16, 3223-3235.   DOI
16 Grabbe, S. and Schwarz, T. (1998). Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19, 37-44.   DOI
17 Gregoire, C., Simova, S., Wang, Y., Sansoni, A., Richelme, S., Schmidt-Giese, A., Simeoni, L., Angelisova, P., Reinhold, D., Schraven, B., et al. (2007). Deletion of the LIME adaptor protein minimally affects T and B cell development and function. Eur. J. Immunol. 37, 3259-3269.   DOI
18 Huang, Y., Clarke, F., Karimi, M., Roy, N.H., Williamson, E.K., Okumura, M., Mochizuki, K., Chen, E.J., Park, T.J., Debes, G.F., et al. (2015). CRK proteins selectively regulate T cell migration into inflamed tissues. J. Clin. Invest. 125, 1019-1032.   DOI
19 Hur, E.M., Son, M., Lee, O.H., Choi, Y.B., Park, C., Lee, H., and Yun, Y. (2003). LIME, a novel transmembrane adaptor protein, associates with p56lck and mediates T cell activation. J. Exp. Med. 198, 1463-1473.   DOI
20 Kawabuchi, M., Satomi, Y., Takao, T., Shimonishi, Y., Nada, S., Nagai, K., Tarakhovsky, A., and Okada, M. (2000). Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 404, 999-1003.   DOI
21 Kinashi, T. (2005). Intracellular signalling controlling integrin activation in lymphocytes. Nat. Rev. Immunol. 5, 546-559.   DOI
22 Klemke, R.L., Leng, J., Molander, R., Brooks, P.C., Vuori, K., and Cheresh, D.A. (1998). CAS/Crk coupling serves as a "molecular switch" for induction of cell migration. J. Cell Biol. 140, 961-972.   DOI
23 Kliche, S., Lindquist, J.A., and Schraven, B. (2004). Transmembrane adapters: structure, biochemistry and biology. Semin. Immunol. 16, 367-377.   DOI
24 Mackay, C.R. (2001). Chemokines: immunology's high impact factors. Nat. Immunol. 2, 95-101.   DOI
25 Marie-Cardine, A., Kirchgessner, H., Bruyns, E., Shevchenko, A., Mann, M. Autschbach, F., Ratnofsky, S., Meuer, S., and Schraven, B. (1999). SHP2-interacting transmembrane adaptor protein (SIT), a novel disulfide-linked dimer regulating human T cell activation. J. Exp. Med. 189, 1181-1194.   DOI
26 Nakae, S., Komiyama, Y., Nambu, A., Sudo, K., Iwase, M., Homma, I., Sekikawa, K., Asano, M., and Iwakura, Y. (2002). Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375-387.   DOI
27 Nguyen, D.H., Giri, B., Collins, G., and Taub, D.D. (2005). Dynamic reorganization of chemokine receptors, cholesterol, lipid rafts, and adhesion molecules to sites of CD4 engagement. Exp. Cell Res. 304, 559-569.   DOI
28 Inngjerdingen, M., Torgersen, K.M., and Maghazachi, A.A. (2002). Lck is required for stromal cell-derived factor 1 alpha (CXCL12)-induced lymphoid cell chemotaxis. Blood 99, 4318-4325.   DOI
29 Ohta, A., Sato, N., Yahata, T., Ohmi, Y., Santa, K., Sato, T., Tashiro, H., Habu, S., and Nishimura, T. (1997). Manipulation of Th1/Th2 balance in vivo by adoptive transfer of antigen-specific Th1 or Th2 cells. J. Immunol. Methods 209, 85-92.   DOI
30 Odaka, M., Matsukura, S., Kuga, H., Kokubu, F., Kasama, T., Kurokawa, M., Kawaguchi, M., Ieki, K., Suzuki, S., Watanabe, S., et al. (2007). Differential regulation of chemokine expression by Th1 and Th2 cytokines and mechanisms of eotaxin/CCL-11 expression in human airway smooth muscle cells. Int. Arch. Allergy Immunol. 143 Suppl 1, 84-88.   DOI
31 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.   DOI
32 Pfrepper, K.I., Marie-Cardine, A., Simeoni, L., Kuramitsu, Y., Leo, A., Spicka, J., Hilgert, I., Scherer, J., and Schraven, B. (2001). Structural and functional dissection of the cytoplasmic domain of the transmembrane adaptor protein SIT (SHP2-interacting transmembrane adaptor protein). Eur. J. Immunol. 31, 1825-1836.   DOI
33 Regelmann, A.G., Danzl, N.M., Wanjalla, C., and Alexandropoulos, K. (2006). The hematopoietic isoform of Cas-Hef1-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking. Immunity 25, 907-918.   DOI
34 Sarkar, S. (1998). Tyrosine phosphorylation and translocation of LAT in platelets. FEBS Lett. 441, 357-360.   DOI
35 Shimonaka, M., Katagiri, K., Nakayama, T., Fujita, N., Tsuruo, T., Yoshie, O., and Kinashi, T. (2003). Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J. Cell Biol. 161, 417-427.   DOI
36 Stromnes, I.M., Cerretti, L.M., Liggitt, D., Harris, R.A., and Goverman, J.M. (2008). Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat. Med. 14, 337-342.   DOI
37 Simeoni, L., Smida, M., Posevitz, V., Schraven, B., and Lindquist, J.A. (2005). Right time, right place: the organization of membrane proximal signaling. Semin. Immunol. 17, 35-49.   DOI
38 Son, M., Park, I., Lee, O.H., Rhee, I., Park, C., and Yun, Y. (2012). LIME mediates immunological synapse formation through activation of VAV. Mol. Cells 33, 407-414.   DOI
39 Staudinger, R., Phogat, S.K., Xiao, X., Wang, X., Dimitrov, D.S., and Zolla-Pazner, S. (2003). Evidence for CD4-enchanced signaling through the chemokine receptor CCR5. J. Biol. Chem. 278, 10389-10392.   DOI
40 Weber, J.R., Orstavik, S., Torgersen, K.M., Danbolt, N.C., Berg, S.F., Ryan, J.C., Tasken, K., Imboden, J.B., and Vaage, J.T. (1998). Molecular cloning of the cDNA encoding pp36, a tyrosine-phosphorylated adaptor protein selectively expressed by T cells and natural killer cells. J. Exp. Med. 187, 1157-1161.   DOI
41 Wong, M., Uddin, S., Majchrzak, B., Huynh, T., Proudfoot, A.E., Platanias, L.C., and Fish, E.N. (2001). Rantes activates Jak2 and Jak3 to regulate engagement of multiple signaling pathways in T cells. J. Biol. Chem. 276, 11427-11431.   DOI
42 Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R.P., and Samelson, L.E. (1998). LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83-92.   DOI
43 Zhang, W., Sommers, C.L., Burshtyn, D.N., Stebbins, C.C., DeJarnette, J.B. Trible, R.P., Grinberg, A., Tsay, H.C., Jacobs, H.M., Kessler, C.M., et al. (1999). Essential role of LAT in T cell development. Immunity 10, 323-332.   DOI