The Development, Activation, Function and Mechanisms of Immunosuppressive Double Negative (DN) T Cells



Double negative (DN) T cells are a subset of T cells, present in the peripheral lymphatic organs and blood in very low numbers (1–2% of lymphocytes) in mice and humans. DN T cells have been shown to inhibit transplant rejection, lymphoma development and graft versus host disease. Furthermore, recent studies have suggested that DN T cells may play a role in the prevention and treatment of autoimmune diseases and bacterial and viral infections. This chapter will discuss the development, activation, functions and mechanism of DN T cells in the suppression of immune responses. The data discussed here suggest that DN T cells might be used as a novel therapy to prevent human transplant rejection, limit tumor survival, inhibit autoimmune disease development and control pathogen infection in an antigen-specific manner.


Treg Cell Suppressive Function Recipient Mouse Double Negative Donor Lymphocyte Infusion 
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This work was supported by the Canadian Institutes of Health Research and the Canadian Cancer Society.


  1. 1.
    van Twuyver, E., Mooijaart, R.J., ten Berge, I.J., van der Horst, A.R., Wilmink, J.M., Kast, W.M., Melief, C.J., and de Waal, L.P., Pretransplantation blood transfusion revisited. N. Engl. J. Med. 1991, 325: 1210–1213.PubMedCrossRefGoogle Scholar
  2. 2.
    van Twuyver, E., Kast, W.M., Mooijaart, R.J.D., Wilmink, J.M., Melief, C.J.M., and de Waal, L.P., Allograft tolerance induction in adult mice associated with functional deletion of specific CTL precursors. Transplantation 1989, 48: 844–847.PubMedCrossRefGoogle Scholar
  3. 3.
    van Twuyver, E., Kast, W.M., Mooijaart, R.J.D., Melief, C.J.M., and de Waal, L.P., Induction of transplantation tolerance by intravenous injection of allogeneic lymphocytes across an H-2 class-II mismatch. Different mechanisms operate in tolerization across an H-2 class- I versus H-2 class-II disparity. Eur. J. Immunol. 1990, 20: 441–444.PubMedCrossRefGoogle Scholar
  4. 4.
    Wood, K.J., Billing, J.S., Binet, I., Bueno, V, and Fry, J., Which donor cells facilitate the induction of specific immunological unresponsiveness to alloantigens in vivo? Transplantation 2002, 73: S16–S18.PubMedCrossRefGoogle Scholar
  5. 5.
    Yang, L., Du, T.B., Khan, Q., and Zhang, L., Mechanisms of long-term donor-specific allograft survival induced by pretransplant infusion of lymphocytes. Blood 1998, 91: 324–330.PubMedGoogle Scholar
  6. 6.
    Zhang, Z.X., Yang, L., Young, K.J., DuTemple, B., and Zhang, L., Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat. Med. 2000, 6: 782–789.PubMedCrossRefGoogle Scholar
  7. 7.
    Chen, W., Zhou, D., Torrealba, J.R., Waddell, T.K., Grant, D., and Zhang, L., Donor lymphocyte infusion induces long-term donor-specific cardiac xenograft survival through activation of recipient double-negative regulatory T cells. J. Immunol. 2005, 175: 3409–3416.PubMedGoogle Scholar
  8. 8.
    Fischer, K., Voelkl, S., Heymann, J., Przybylski, G.K., Mondal, K., Laumer, M., Kunz-Schughart, L., Schmidt, C.A., Andreesen, R., and Mackensen, A., Isolation and characterization of human antigen-specific TCR alpha beta+ CD4(−)CD8− double-negative regulatory T cells. Blood 2005, 105: 2828–2835.PubMedCrossRefGoogle Scholar
  9. 9.
    Itoh, M., Takahashi, T., Sakaguchi, N., Kuniyasu, Y., Shimizu, J., Otsuka, F., and Sakaguchi, S., Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 1999, 162: 5317–5326.PubMedGoogle Scholar
  10. 10.
    Sakaguchi, S., Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol. 2005, 6: 345–352.PubMedCrossRefGoogle Scholar
  11. 11.
    Fontenot, J.D. and Rudensky, A.Y., A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 2005, 6: 331–337.PubMedCrossRefGoogle Scholar
  12. 12.
    Sakaguchi, S., Takahashi, T., and Nishizuka, Y., Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J. Exp. Med. 1982, 156: 1577–1586.PubMedCrossRefGoogle Scholar
  13. 13.
    Watanabe, N., Wang, Y.H., Lee, H.K., Ito, T., Wang, Y.H., Cao, W., and Liu, Y.J., Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 2005, 436: 1181–1185.PubMedCrossRefGoogle Scholar
  14. 14.
    Cozzo, C., Lerman, M.A., Boesteanu, A., Larkin, J., III, Jordan, M.S., and Caton, A.J., Selection of CD4+CD25+ regulatory T cells by self-peptides. Curr. Top. Microbiol. Immunol. 2005, 293: 3–23.PubMedGoogle Scholar
  15. 15.
    Cozzo, C., Larkin, J., III, and Caton, A.J., Cutting edge: self-peptides drive the peripheral expansion of CD4+CD25+ regulatory T cells. J. Immunol. 2003, 171: 5678–5682.PubMedGoogle Scholar
  16. 16.
    Ribot, J., Romagnoli, P., and van Meerwijk, J.P., Agonist ligands expressed by thymic epithelium enhance positive selection of regulatory T lymphocytes from precursors with a normally diverse TCR repertoire. J. Immunol. 2006, 177: 1101–1107.PubMedGoogle Scholar
  17. 17.
    Cabarrocas, J., Cassan, C., Magnusson, F., Piaggio, E., Mars, L., Derbinski, J., Kyewski, B., Gross, D.A., Salomon, B.L., Khazaie, K., Saoudi, A., and Liblau, R.S., Foxp3+ CD25+ regulatory T cells specific for a neo-self-antigen develop at the double-positive thymic stage. Proc. Natl. Acad. Sci. U. S. A. 2006, 103: 8453–8458.PubMedCrossRefGoogle Scholar
  18. 18.
    Karim, M., Kingsley, C.I., Bushell, A.R., Sawitzki, B.S., and Wood, K.J., Alloantigen-induced CD25+CD4+ regulatory T cells can develop in vivo from CD25-CD4+ precursors in a thymus-independent process. J. Immunol. 2004, 172: 923–928.PubMedGoogle Scholar
  19. 19.
    Aifantis, I., Bassing, C.H., Garbe, A.I., Sawai, K., Alt, F.W., and von Boehmer, H., The E{delta} enhancer controls the generation of CD4-CD8- {alpha}{beta}TCR-expressing T cells that can give rise to different lineages of {alpha}{beta} T cells. J. Exp. Med. 2006, 203: 1543–1550.PubMedCrossRefGoogle Scholar
  20. 20.
    Wang, R., Wang-Zhu, Y., and Grey, H., Interactions between double positive thymocytes and high affinity ligands presented by cortical epithelial cells generate double negative thymocytes with T cell regulatory activity. Proc. Natl. Acad. Sci. U. S. A. 2002, 99: 2181–2186.PubMedCrossRefGoogle Scholar
  21. 21.
    Yamagiwa, S., Sugahara, S., Shimizu, T., Iwanaga, T., Yoshida, Y., Honda, S., Watanabe, H., Suzuki, K., Asakura, H., and Abo, T., The primary site of CD4− 8− B220+ alphabeta T cells in lpr mice: the appendix in normal mice. J. Immunol. 1998, 160: 2665–2674.PubMedGoogle Scholar
  22. 22.
    Johansson, M. and Lycke, N., A unique population of extrathymically derived alpha beta TCR+CD4–CD8– T cells with regulatory functions dominates the mouse female genital tract. J. Immunol. 2003, 170: 1659–1666.PubMedGoogle Scholar
  23. 23.
    Rharbaoui, F., Bruder, D., Vidakovic, M., Ebensen, T., Buer, J., and Guzman, C.A., Characterization of a B220+ lymphoid cell subpopulation with immune modulatory functions in nasal-associated lymphoid tissues. J. Immunol. 2005, 174: 1317–1324.PubMedGoogle Scholar
  24. 24.
    Halder, R.C., Kawamura, T., Bannai, M., Watanabe, H., Kawamura, H., Mannoor, M.K., Morshed, S.R., and Abo, T., Intensive generation of NK1.1- extrathymic T cells in the liver by injection of bone marrow cells isolated from mice with a mutation of polymorphic major histocompatibility complex antigens. Immunology 2001, 102: 450–459.PubMedCrossRefGoogle Scholar
  25. 25.
    Ohteki, T., Seki, S., Abo, T., and Kumagai, K., Liver is a possible site for the proliferation of abnormal CD3+4–8 double-negative lymphocytes in autoimmune MRL-lpr/lpr mice. J. Exp. Med. 1990, 172: 7–12.PubMedCrossRefGoogle Scholar
  26. 26.
    Ford, M.S., Zhang, Z.X., Chen, W., and Zhang, L., Double-negative T regulatory cells can develop outside the thymus and do not mature from CD8+ T cell precursors. J. Immunol. 2006, 177: 2803–2809.PubMedGoogle Scholar
  27. 27.
    Erard, F., Wild, M.T., Garcia-Sanz, J.A., and Le Gros, G., Switch of CD8 T cells to noncytolytic CD8CD4 cells that make TH2 cytokines and help B cells. Science 1993, 260: 1802–1805.PubMedCrossRefGoogle Scholar
  28. 28.
    Young, K.J., Yang, L.M., Phillips, M.J., and Zhang, L., Donor-lymphocyte infusion induces tolerance by activating systemic and graft-infiltrating double negative T regulatory cells. Blood 2002, 100: 3408–3414.PubMedCrossRefGoogle Scholar
  29. 29.
    Chen, W.H., Ford, M., Young, K.J., Cybulsky, M., and Zhang, L., The role of DN regulatory T cells in long-term cardiac xenograft survival Induced by pretransplant donor lymphocyte infusion and a short course of depleting anti-CD4 antibody. J. Immunol. 2003, 170: 1846–1853.PubMedGoogle Scholar
  30. 30.
    Harty, J.T. and Badovinac, V.P., Influence of effector molecules on the CD8(+) T cell response to infection. Curr. Opin. Immunol. 2002, 14: 360–365.PubMedCrossRefGoogle Scholar
  31. 31.
    Khan, Q., Penninger, J.M., Yang, L.M., Marra, L.E.K.I., and Zhang, L., Regulation of apoptosis in mature αβ+ CD4CD8 antigen-specific suppressor T-cell clones. J. Immunol. 1999, 162: 5860–5867.PubMedGoogle Scholar
  32. 32.
    Chen, W., Ford, M.S., Young, K.J., and Zhang, L., The role and mechanisms of double negative regulatory T cells in the suppression of immune responses. Cell Mol. Immunol. 2004, 1: 328–335.PubMedGoogle Scholar
  33. 33.
    Zhang, Z.X., Stanford, W.L., and Zhang, L., Ly-6A is critical for the function of double negative regulatory T cells. Eur. J. Immunol. 2002, 32: 1584–1592.Google Scholar
  34. 34.
    Ford, M.S., Young, K.J., Zhang, Z.X., Ohashi, P.S., and Zhang, L., The immune regulatory function of lymphoproliferative double negative T cells in vitro and in vivo. J. Exp. Med. 2002, 196: 261–267.PubMedCrossRefGoogle Scholar
  35. 35.
    Giese, T. and Davidson, W.F., Chronic treatment of C3H-lpr/lpr and C3H-gld/gld mice with anti-CD8 monoclonal antibody prevents the accumulation of double negative T cells but not autoantibody production. J. Immunol. 1994, 152: 2000–2010.Google Scholar
  36. 36.
    Polster, K., Walker, A., Fildes, J., Entwistle, G., Yonan, N., Hutchinson, I.V., and Leonard, C.T., CD4-veCD8-ve CD30+ve T cells are detectable in human lung transplant patients and their proportion of the lymphocyte population after in vitro stimulation with donor spleen cells correlates with preservation of lung physiology. Transplant. Proc. 2005, 37: 2257–2260.PubMedCrossRefGoogle Scholar
  37. 37.
    Priatel, J.J., Utting, O., and Teh, H.S., TCR/self-antigen interactions drive double-negative T cell peripheral expansion and differentiation into suppressor cells. J. Immunol. 2001, 167: 6188–6194.PubMedGoogle Scholar
  38. 38.
    Benihoud, K., Bonardelle, D., Bobe, P., and Kiger, N., MRL/lpr CD4- CD8- and CD8+ T cells, respectively, mediate Fas-dependent and perforin cytotoxic pathways. Eur. J. Immunol. 1997, 27: 415–420.PubMedCrossRefGoogle Scholar
  39. 39.
    Canale, V.C. and Smith, C.H., Chronic lymphadenopathy simulating malignant lymphoma. J. Pediatr. 1967, 70: 891–899.PubMedCrossRefGoogle Scholar
  40. 40.
    Bettinardi, A., Brugnoni, D., Quiros-Roldan, E., Malagoli, A., La Grutta, S., Correra, A., and Notarangelo, L.D., Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood 1997, 89: 902–909.PubMedGoogle Scholar
  41. 41.
    Brooks, E.G., Balk, S.P., Aupeix, K., Colonna, M., Strominger, J.L., and Groh-Spies, V., Human T-cell receptor (TCR) alpha/beta + CD4–CD8– T cells express oligoclonal TCRs, share junctional motifs across TCR V beta-gene families, and phenotypically resemble memory T cells. Proc. Natl. Acad. Sci. U. S. A. 1993, 90: 11787–11791.PubMedCrossRefGoogle Scholar
  42. 42.
    Martinez, C., Marcos, M.A., de Alboran, I.M., Alonso, J.M., de Cid, R., Kroemer, G., and Coutinho, A., Functional double-negative T cells in the periphery express T cell receptor V beta gene products that cause deletion of single-positive T cells. Eur. J. Immunol. 1993, 23: 250–254.PubMedCrossRefGoogle Scholar
  43. 43.
    Ford, M.S., Chen, W., Wong, S., Li, C., Vanama, R., Elford, A.R., Asa, S.L., Ohashi, P.S., and Zhang, L., Peptide-activated double-negative T cells can prevent autoimmune type-1 diabetes development. Eur. J. Immunol. 2007, 37: 2234–2241.PubMedCrossRefGoogle Scholar
  44. 44.
    Young, K.J., Kay, L.S., Phillips, M.J., and Zhang, L., Antitumor activity mediated by double-negative T cells. Cancer Res. 2003, 63: 8014–8021.PubMedGoogle Scholar
  45. 45.
    Young, K.J., Du Temple, B., Phillips, M.J., and Zhang, L., Inhibition of graft versus host disease by double negative regulatory T cells. J. Immunol. 2003, 171: 134–141.PubMedGoogle Scholar
  46. 46.
    Abraham, V.S., Sachs, D.H., and Sykes, M., Mechanism of protection from graft-versus-host disease mortality by IL- 2. III. Early reductions in donor T cell subsets and expansion of a CD3+CD4CD8 cell population. J. Immunol. 1992, 148: 3746–3752.PubMedGoogle Scholar
  47. 47.
    Bruley-Rosset, M., Miconnet, I., Canon, C., and Halle-Pannenko, O., Mlsa generated suppressor cells. I. Suppression is mediated by double- negative (CD3+CD5+CD4-CD8-) alpha/beta T cell receptor-bearing cells. J. Immunol. 1990, 145: 4046–4052.PubMedGoogle Scholar
  48. 48.
    Prins, R.M., Incardona, F., Lau, R., Lee, P., Claus, S., Zhang, W., Black, K.L., and Wheeler, C.J., Characterization of defective CD4–CD8– T cells in murine tumors generated independent of antigen specificity. J. Immunol. 2004, 172: 1602–1611.PubMedGoogle Scholar
  49. 49.
    Matsuo, R., Herndon, D.N., Kobayashi, M., Pollard, R.B., and Suzuki, F., CD4 CD8 TCR αβ+ suppressor T cells demonstrated in mice 1 day after thermal injury. J. Trauma 1997, 42: 635–640.PubMedCrossRefGoogle Scholar
  50. 50.
    Kadena, T., Matsuzaki, G., Fujise, S., Kishihara, K., Takimoto, H., Sasaki, M., Beppu, M., Nakamura, S., and Nomoto, K., TCR alpha beta+ CD4– CD8– T cells differentiate extrathymically in an lck-independent manner and participate in early response against Listeria monocytogenes infection through interferon-gamma production. Immunology 1997, 91: 511–519.PubMedCrossRefGoogle Scholar
  51. 51.
    Cowley, S.C., Hamilton, E., Frelinger, J.A., Su, J., Forman, J., and Elkins, K.L., CD4–CD8– T cells control intracellular bacterial infections both in vitro and in vivo. J. Exp. Med. 2005, 202: 309–319.PubMedCrossRefGoogle Scholar
  52. 52.
    Carulli, G., Lagomarsini, G., Azzara, A., Testi, R., Riccioni, R., and Petrini, M., Expansion of TcRalphabeta+CD3+CD4–CD8– (CD4/CD8 double-negative) T lymphocytes in a case of staphylococcal toxic shock syndrome. Acta Haematol. 2004, 111: 163–167.PubMedCrossRefGoogle Scholar
  53. 53.
    Hossain, M.S., Takimoto, H., Ninomiya, T., Yoshida, H., Kishihara, K., Matsuzaki, G., Kimura, G., and Nomoto, K., Characterization of CD4– CD8– CD3+ T-cell receptor-alpha/beta+ T cells in murine cytomegalovirus infection. Immunology 2000, 101: 19–29.PubMedCrossRefGoogle Scholar
  54. 54.
    Mathiot, N.D., Krueger, R., French, M.A., and Price, P., Percentage of CD3+CD4–CD8–gammadeltaTCR- T cells is increased HIV disease. AIDS Res. Hum. Retroviruses 2001, 17: 977–980.PubMedCrossRefGoogle Scholar
  55. 55.
    Moreau, J.F., Taupin, J.L., Dupon, M., Carron, J.C., Ragnaud, J.M., Marimoutou, C., Bernard, N., Constans, J., Texier-Maugein, J., Barbeau, P., Journot, V., Dabis, F., Bonneville, M., and Pellegrin, J.L., Increases in CD3+CD4–CD8– T lymphocytes in AIDS patients with disseminated Mycobacterium avium-intracellulare complex infection. J. Infect. Dis. 1996, 174: 969–976.PubMedCrossRefGoogle Scholar
  56. 56.
    Lee, B.P., Mansfield, E., Hsieh, S.C., Hernandez-Boussard, T., Chen, W., Thomson, C.W., Ford, M.S., Bosinger, S.E., Der, S., Zhang, Z.X., Zhang, M., Kelvin, D.J., Sarwal, M.M., and Zhang, L., Expression profiling of murine double-negative regulatory T cells suggest mechanisms for prolonged cardiac allograft survival. J. Immunol. 2005, 174:4535–4544.PubMedGoogle Scholar
  57. 57.
    Zhang, Z.X., Ma, Y., Wang, H., Arp, J., Jiang, J., Huang, X., He, K.M., Garcia, B., Madrenas, J., and Zhong, R., Double-negative T cells, activated by xenoantigen, lyse autologous B and T cells using a perforin/granzyme-dependent, fas-fas ligand-independent pathway. J. Immunol. 2006, 177: 6920–6929.PubMedGoogle Scholar
  58. 58.
    Hamad, A.R., Mohamood, A.S., Trujillo, C.J., Huang, C.T., Yuan, E., and Schneck, J.P., B220+ double-negative T cells suppress polyclonal T cell activation by a Fas-independent mechanism that involves inhibition of IL-2 production. J. Immunol. 2003, 171: 2421–2426.PubMedGoogle Scholar
  59. 59.
    Powrie, F., Carlino, J., Leach, M.W., Mauze, S., and Coffman, R.L., A critical role for transforming growth factor-B but not interleukin 4 in the suppression of T helper type1-mediated colitis by CD45RBlow CD4+ T cells. J. Exp. Med. 1996, 183: 2669–2674.PubMedCrossRefGoogle Scholar
  60. 60.
    Asseman, C., Mauze, S., Leach, M.W., Coffman, R.L., and Powrie, F., An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 1999, 190: 995–1004.PubMedCrossRefGoogle Scholar
  61. 61.
    Seddon, B. and Mason, D., Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor β and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4+CD8- Thymocytes. J. Exp. Med. 1999, 189: 279–288.PubMedCrossRefGoogle Scholar
  62. 62.
    Kitani, A., Chua, K., Nakamura, K., and Strober, W., Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells. J. Immunol. 2000, 165: 691–702.PubMedGoogle Scholar
  63. 63.
    Groux, H., O'Garra, A., Bigler, M., Rouleau, M., Antonenko, S., de Vries, J.E., and Roncarolo, M.G., A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997, 389: 737–742.PubMedCrossRefGoogle Scholar
  64. 64.
    Cavani, A., Nasorri, F., Prezzi, C., Sebastiani, S., Albanesi, C., and Girolomoni, G., Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. J. Invest Dermatol. 2000, 114: 295–302.PubMedCrossRefGoogle Scholar
  65. 65.
    Lee, B.P., Chen, W., Shi, H., Der, S.D., Forster, R., and Zhang, L., CXCR5/CXCL13 interaction is important for double-negative regulatory T cell homing to cardiac allografts. J. Immunol. 2006, 176: 5276–5283.PubMedGoogle Scholar
  66. 66.
    Thomson, C.W., Teft, W.A., Chen, W., Lee, B.P., Madrenas, J., and Zhang, L., FcR{gamma} Presence in TCR Complex of Double-Negative T Cells Is Critical for Their Regulatory Function. J. Immunol. 2006, 177: 2250–2257.PubMedGoogle Scholar
  67. 67.
    Young, K. and Zhang, L., The nature and mechanisms of DN regulatory T-Cell mediated suppression. Hum. Immunol. 2002, 63: 926.PubMedCrossRefGoogle Scholar
  68. 68.
    Hudrisier, D., Riond, J., Mazarguil, H., Gairin, J.E., and Joly, E., Cutting edge: CTLs rapidly capture membrane fragments from target cells in a TCR signaling-dependent manner. J. Immunol. 2001, 166: 3645–3649.PubMedGoogle Scholar
  69. 69.
    Stinchcombe, J.C., Bossi, G., Booth, S., and Griffiths, G.M., The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 2001, 15: 751–761.PubMedCrossRefGoogle Scholar
  70. 70.
    Hwang, I., Huang, J.F., Kishimoto, H., Brunmark, A., Peterson, P.A., Jackson, M.R., Surh, C.D., Cai, Z., and Sprent, J., T cells can use either T cell receptor or CD28 receptors to absorb and internalize cell surface molecules derived from antigen-presenting cells. J. Exp. Med. 2000, 191: 1137–1148.PubMedCrossRefGoogle Scholar
  71. 71.
    Sabzevari, H., Kantor, J., Jaigirdar, A., Tagaya, Y., Naramura, M., Hodge, J., Bernon, J., and Schlom, J., Acquisition of CD80 (b7-1) by T cells. J. Immunol. 2001, 166: 2505–2513.PubMedGoogle Scholar
  72. 72.
    Patel, D.M., Arnold, P.Y., White, G.A., Nardella, J.P., and Mannie, M.D., Class II MHC/peptide complexes are released from APC and are acquired by T cell responders during specific antigen recognition. J. Immunol. 1999, 163: 5201–5210.PubMedGoogle Scholar
  73. 73.
    Huang, J.F., Yang, Y., Sepulveda, H., Shi, W., Hwang, I., Peterson, P.A., Jackson, M.R., Sprent, J., and Cai, Z., TCR-Mediated internalization of peptide-MHC complexes acquired by T cells. Science 1999, 286: 952–954.PubMedCrossRefGoogle Scholar
  74. 74.
    Batista, F.D., Iber, D., and Neuberger, M.S., B cells acquire antigen from target cells after synapse formation. Nature 2001, 411: 489–494.PubMedCrossRefGoogle Scholar
  75. 75.
    Harshyne, L.A., Watkins, S.C., Gambotto, A., and Barratt-Boyes, S.M., Dendritic cells acquire antigens from live cells for cross-presentation to CTL. J. Immunol. 2001, 166: 3717–3723.PubMedGoogle Scholar
  76. 76.
    Hwang, I., Shen, X., and Sprent, J., Direct stimulation of naive T cells by membrane vesicles from antigen-presenting cells: distinct roles for CD54 and B7 molecules. Proc. Natl. Acad. Sci. U. S. A. 2003, 100: 6670–6675.PubMedCrossRefGoogle Scholar
  77. 77.
    Tsang, J.Y., Chai, J.G., and Lechler, R., Antigen presentation by mouse CD4+ T cells involving acquired MHC class II:peptide complexes: another mechanism to limit clonal expansion? Blood 2003, 101: 2704–2710.PubMedCrossRefGoogle Scholar
  78. 78.
    Kennedy, R., Undale, A.H., Kieper, W.C., Block, M.S., Pease, L.R., and Celis, E., Direct cross-priming by Th lymphocytes generates memory cytotoxic T cell responses. J. Immunol. 2005, 174: 3967–3977.PubMedGoogle Scholar
  79. 79.
    Zhou, J., Tagaya, Y., Tolouei-Semnani, R., Schlom, J., and Sabzevari, H., Physiological relevance of antigen presentasome (APS), an acquired MHC/costimulatory complex, in the sustained activation of CD4+ T cells in the absence of APCs. Blood 2005, 105: 3238–3246.PubMedCrossRefGoogle Scholar
  80. 80.
    Game, D.S., Rogers, N.J., and Lechler, R.I., Acquisition of HLA-DR and costimulatory molecules by T cells from allogeneic antigen presenting cells. Am. J. Transplant. 2005, 5: 1614–1625.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Departments of Laboratory Medicine and Pathobiology, Immunology, Toronto General Research InstituteUniversity Health Network, University of Toronto TMDT 2-807TorontoCanada

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