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Engagement of CD44 up-regulates Fas Ligand expression on T cells leading to activation-induced cell death

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Abstract

Activation-induced cell death (AICD) plays a pivotal role in self-tolerance by deleting autoreactive T cells, but a defect of AICD results in expansion of autoreactive T cells and is deeply involved in the pathogenesis of rheumatoid arthritis. Although the process of AICD is mainly mediated by Fas Ligand (FasL)/Fas signaling, it remains unclear what induces FasL expression on T cells. In the present study, we found that CD44 was the most potent stimulator of FasL expression on human peripheral T cells. CD44 cross-linking rapidly up-regulated FasL expression on the T cell surface by delivery from the cytoplasm without new FasL protein synthesis. This up-regulation of FasL was mediated by activation of a tyrosine kinase, IP3 receptor-dependent Ca2+ mobilization and actin cytoskeletal rearrangements. Furthermore, AICD induced by CD3 restimulation was inhibited by hyaluronidase as well as by soluble Fas, indicating an interaction between membrane-bound hyaluronan and the cell surface CD44 was involved in the up-regulation of FasL expression on T cells and subsequent AICD. We therefore propose that the engagement of CD44 on T cells can eliminate autoreactive T cells by expression of FasL and FasL-mediated AICD.

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References

  1. Lee DM, Weinblatt ME (2001) Rheumatoid arthritis. The Lancet 358:903–11

    Article  CAS  Google Scholar 

  2. Nagata S (1997) Apoptosis by death factor. Cell 88:355–65

    Article  CAS  PubMed  Google Scholar 

  3. Green DR, Scott DW (1994) Activation-induced apoptosis in lymphocytes. Curr Opin Immunol 6:476–87

    Article  CAS  PubMed  Google Scholar 

  4. Russell JH (1995) Activation-induced death of mature T cells in the regulation of immune responses. Curr Opin Immunol 7:382–88

    Article  CAS  PubMed  Google Scholar 

  5. Delovitch TL, Singh B (1997) The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7:727–38

    Article  CAS  PubMed  Google Scholar 

  6. Salojin KV, Zhang J, Madrenas J, Delovitch TL (1998) T-cell anergy and altered T-cell receptor signaling: effects on autoimmune disease. Immunol Today 19:468–73

    Article  CAS  PubMed  Google Scholar 

  7. Nagata S, Suda T (1995) Fas and Fas ligand: lpr and gld mutations. Immunol Today 16:39–3

    Article  CAS  PubMed  Google Scholar 

  8. Fisher GH, Rosenberg FJ, Straus SE et al (1995) Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81:935–46

    Article  Google Scholar 

  9. Rieux-Laucat F, Le Deist F, Hivroz C et al (1995) Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268:1347–349

    Article  CAS  PubMed  Google Scholar 

  10. Salmon M, Scheel-Toellner D, Huissoon AP et al (1997) Inhibition of T Cell Apoptosis in the Rheumatoid Synovium. J Clin Invest 99:439–46

    Article  CAS  PubMed  Google Scholar 

  11. Okazaki H, Sato H, Kamimura T et al (2000) In vitro and in vivo inhibition of activation induced T cell apoptosis by bucillamine. J Rheumatol 27:1358–364

    CAS  PubMed  Google Scholar 

  12. Zhang J, Bardos T, Mikecz K, Finnegan A, Glant TT (2001) Impaired fas signaling pathway is involved in defective T cell apoptosis in autoimmune murine arthritis. J Immunol 166:4981–986

    CAS  PubMed  Google Scholar 

  13. Tang X, Yocum DE, Dejonghe D, Nordensson K, Lake DF, Richard J (2004) Increased activation-induced cell death in peripheral lymphocytes of rheumatoid arthritis patients: the mechanism of action. Immunology 112:496–05

    Article  PubMed  Google Scholar 

  14. Brunner T, Mogil RJ, LaFace D et al (1995) Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373:441–44

    Article  CAS  PubMed  Google Scholar 

  15. Dhein J, Walczak H, Baumler C, Debatin KM, Krammer PH (1995) Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373:438–41

    Article  CAS  PubMed  Google Scholar 

  16. Ju ST, Panka DJ, Cui H et al (1995) Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373:444–48

    Article  CAS  PubMed  Google Scholar 

  17. Schneider P, Holler N, Bodmer JL et al (1998) Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J Exp Med 187:1205–213

    Article  CAS  PubMed  Google Scholar 

  18. Tanaka M, Itai T, Adachi M, Nagata S (1998) Downregulation of Fas ligand by shedding. Nat Med 4:31–6

    Article  CAS  PubMed  Google Scholar 

  19. Montel AH, Bochan MR, Hobbs JA, Lynch DH, Brahmi Z (1995) Fas involvement in cytotoxicity mediated by human NK cells. Cell Immunol 166:236–46

    Article  CAS  PubMed  Google Scholar 

  20. Suda T, Okazaki T, Naito Y et al (1995) Expression of the Fas ligand in cells of T cell lineage. J Immunol 154:3806–813

    CAS  PubMed  Google Scholar 

  21. Bossi G, Griffiths GM (1999) Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells. Nat Med 5:90–6

    Article  CAS  PubMed  Google Scholar 

  22. Grakoui A, Bromley SK, Sumen C, et al. (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285:221–27

    Article  CAS  PubMed  Google Scholar 

  23. Foger N, Marhaba R, Zoller M (2001) Involvement of CD44 in cytoskeleton rearrangement and raft reorganization in T cells. J Cell Sci 114:1169–178

    CAS  PubMed  Google Scholar 

  24. Doussau F, Gasman S, Humeau Y et al (2000) A Rho-related GTPase is involved in Ca(2+)-dependent neurotransmitter exocytosis. J Biol Chem 275:7764–770

    Article  CAS  PubMed  Google Scholar 

  25. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B (1990) CD44 is the principal cell surface receptor for hyaluronate. Cell 61:1303–313

    Article  CAS  PubMed  Google Scholar 

  26. Mummert ME, Mummert D, Edelbaum D, Hui F, Matsue H, Takashima A (2002) Synthesis and surface expression of hyaluronan by dendritic cells and its potential role in antigen presentation. J Immunol 169:4322–331

    CAS  PubMed  Google Scholar 

  27. DeGrendele HC, Estess P, Siegelman MH (1997) Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 278:672–75

    Article  CAS  PubMed  Google Scholar 

  28. Nagaya H, Ymagata T, Ymagata S et al (1999) Examination of synovial fluid and serum hyaluronidase activity as a joint marker in rheumatoid arthritis and osteoarthritis patients (by zymography). Ann Rheum Dis 58:186–88

    Article  CAS  PubMed  Google Scholar 

  29. Girard N, Maingonnat C, Bertrand P, Tilly H, Vannier JP, Delpech B (2002) Human monocytes synthesize hyaluronidase. Br J Haematol 119:199–03

    Article  CAS  PubMed  Google Scholar 

  30. Flanagan BF, Dalchau R, Allen AK, Daar AS, Fabre JW (1989) Chemical composition and tissue distribution of the human CDw44 glycoprotein. Immunology 67:167–75

    CAS  PubMed  Google Scholar 

  31. Haynes BF, Telen MJ, Hale LP, Denning SM (1989) CD44–a molecule involved in leukocyte adherence and T-cell activation. Immunol Today 10:423–28

    Article  CAS  PubMed  Google Scholar 

  32. Huet S, Groux H, Caillou B, Valentin H, Prieur AM, Bernard A (1989) CD44 contributes to T cell activation. J Immunol 143:798–01

    CAS  PubMed  Google Scholar 

  33. Day AJ, Prestwich GD (2002) Hyaluronan-binding proteins: tying up the giant. J Biol Chem 277:4585–588

    Article  CAS  PubMed  Google Scholar 

  34. DeGrendele HC, Kosfiszer M, Estess P, Siegelman MH (1997) CD44 activation and associated primary adhesion is inducible via T cell receptor stimulation. J Immunol 159:2549–553

    CAS  PubMed  Google Scholar 

  35. Termeer C, Averbeck M, Hara H et al (2003) Targeting dendritic cells with CD44 monoclonal antibodies selectively inhibits the proliferation of naive CD4+T-helper cells by induction of FAS-independent T-cell apoptosis. Immunology 109:32–0

    Article  CAS  PubMed  Google Scholar 

  36. Laurent TC, Fraser JR (1992) Hyaluronan. Faseb J 6:2397–404

    CAS  PubMed  Google Scholar 

  37. Chen D, McKallip RJ, Zeytun A et al (2001) CD44-deficient mice exhibit enhanced hepatitis after concanavalin A injection: evidence for involvement of CD44 in activation-induced cell death. J Immunol 166:5889–897

    CAS  PubMed  Google Scholar 

  38. Bourguignon LY, Zhu H, Shao L, Chen YW (2001) CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration. J Biol Chem 276:7327–336

    Article  CAS  PubMed  Google Scholar 

  39. Katoh H, Negishi M (2003) RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature 424:461–64

    Article  CAS  PubMed  Google Scholar 

  40. Thorne RF, Legg JW, Isacke CM (2004) The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events. J Cell Sci 117:373–80

    Article  CAS  PubMed  Google Scholar 

  41. Bourguignon LY, Zhu H, Shao L, Chen YW (2000) Ankyrin-Tiam1 interaction promotes Rac1 signaling and metastatic breast tumor cell invasion and migration. J Cell Biol 150:177–91

    Article  CAS  PubMed  Google Scholar 

  42. Yoshida M, Sai S, Marumo K et al (2004) Expression analysis of three isoforms of hyaluronan synthase and hyaluronidase in the synovium of knees in osteoarthritis and rheumatoid arthritis by quantitative real-time reverse transcriptase polymerase chain reaction. Arthritis Res Ther 6:R514–20

    Article  CAS  PubMed  Google Scholar 

  43. Naor D, Nedvetzki S (2003) CD44 in rheumatoid arthritis. Arthritis Res Ther 5:105–15

    Article  CAS  PubMed  Google Scholar 

  44. Fujii K, Tanaka Y, Hubscher S, Saito K, Ota T, Eto S (1999) Crosslinking of CD44 on rheumatoid synovial cells augment interleukin 6 production. Lab Invest 79:1439–446

    CAS  PubMed  Google Scholar 

  45. Fujii K, Tanaka Y, Hubscher S, Saito K, Ota T, Eto S (1999) Cross-linking of CD44 on rheumatoid synovial cells up-regulates VCAM-1. J Immunol 162:2391–398

    CAS  PubMed  Google Scholar 

  46. Knudson W, Casey B, Nishida Y, Eger W, Kuettner KE, Knudson CB (2000) Hyaluronan oligosaccharides perturb cartilage matrix homeostasis and induce chondrocytic chondrolysis. Arthritis Rheum 43:1165–174

    Article  CAS  PubMed  Google Scholar 

  47. Baier A, Meineckel I, Gay S, Pap T (2003) Apoptosis in rheumatoid arthritis. Curr Opin Rheumatol 15:274–79

    Article  CAS  PubMed  Google Scholar 

  48. Nedvetzki S, Walmsley M, Alpert E, Williams RO, Feldmann M, Naor D (1999) CD44 involvement in experimental collagen-induced arthritis (CIA). J Autoimmun 13:39–7

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Kazuhisa Nakano.

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Grant support: Scientific Research by the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan and University of Occupational and Environmental Health, Japan.

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Nakano, K., Saito, K., Mine, S. et al. Engagement of CD44 up-regulates Fas Ligand expression on T cells leading to activation-induced cell death. Apoptosis 12, 45–54 (2007). https://doi.org/10.1007/s10495-006-0488-8

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  • DOI: https://doi.org/10.1007/s10495-006-0488-8

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