About this Journal Submit a Manuscript Table of Contents
ISRN Infectious Diseases
Volume 2013 (2013), Article ID 801975, 11 pages
http://dx.doi.org/10.5402/2013/801975
Review Article

The Development of Unconventional Extrathymic Activated CD4+CD8+ T Cells in Chagas Disease

Instituto de Microbiologia Prof. Paulo de Góes (IMPPG), Universidade Federal do Rio de Janeiro (UFRJ), CCS, Bloco D, Sala-D1-035, Avenida Carlos Chagas Filho, 373-Cidade Universitária, 21.941-902 Ilha do Fundão, Rio de Janeiro, RJ 21.941-902, Brazil

Received 10 April 2013; Accepted 2 June 2013

Academic Editors: Y.-H. Gan, H. Hisaeda, and Y. Lai

Copyright © 2013 Alexandre Morrot. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Y. Lai and M. Kondo, “T and B lymphocyte differentiation from hematopoietic stem cell,” Seminars in Immunology, vol. 20, no. 4, pp. 207–212, 2008. View at Publisher · View at Google Scholar · View at Scopus
  2. T. Okada, S. Moriyama, and M. Kitano, “Differentiation of germinal center B cells and follicular helper T cells as viewed by tracking Bcl6 expression dynamics,” Immunological Reviews, vol. 247, no. 1, pp. 120–132, 2012. View at Publisher · View at Google Scholar · View at Scopus
  3. D. J. Izon, R. L. Boyd, G. A. Waanders, and A. Kelso, “The myelopoietic inducing potential of mouse thymic stromal cells,” Cellular Immunology, vol. 124, no. 2, pp. 264–277, 1989. View at Publisher · View at Google Scholar · View at Scopus
  4. W. van Ewijk, “The thymus: ‘interactive teaching during lymphopoiesis’,” Immunology Letters, vol. 138, no. 1, pp. 7–8, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. H. T. Petrie and J. C. Zúñiga-Pflücker, “Zoned out: functional mapping of stromal signaling microenvironments in the thymus,” Annual Review of Immunology, vol. 25, pp. 649–679, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. S. Zuklys, C. E. Mayer, S. Zhanybekova et al., “MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection,” Journal of Immunology, vol. 189, no. 8, pp. 3894–3904, 2012. View at Publisher · View at Google Scholar
  7. K. W. Pyke, H. M. Dosch, M. M. Ipp, and E. W. Gelfand, “Demonstration of an intrathymic defect in a case of severe combined immunodeficiency disease,” The New England Journal of Medicine, vol. 293, no. 9, pp. 424–428, 1975. View at Scopus
  8. K. S. Landreth, K. McCoy, and J. Clagett, “Deficiency in cells expressing terminal transferase in autoimmune (motheaten) mice,” Nature, vol. 290, no. 5805, pp. 409–411, 1981. View at Scopus
  9. T. Katagiri, P. L. Cohen, and R. A. Eisenberg, “The lpr gene causes an intrinsic T cell abnormality that is required for hyperproliferation,” Journal of Experimental Medicine, vol. 167, no. 3, pp. 741–751, 1988. View at Scopus
  10. H. M. Georgiou and T. E. Mandel, “Induction of insulitis in athymic (nude) mice: the effect of NOD thymus and pancreas transplantation,” Diabetes, vol. 44, no. 1, pp. 49–59, 1995. View at Scopus
  11. H. S. Scott, M. Heino, P. Peterson et al., “Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins,” Molecular Endocrinology, vol. 12, no. 8, pp. 1112–1119, 1998. View at Scopus
  12. A. L. Fletcher, A. Calder, M. N. Hince, R. L. Boyd, and A. P. Chidgey, “The contribution of thymic stromal abnormalities to autoimmune disease,” Critical Reviews in Immunology, vol. 31, no. 3, pp. 171–187, 2011. View at Scopus
  13. C. Schmitt, S. Ktorza, S. Sarun, C. Blanc, R. de Jong, and P. Debre, “CD34-expressing human thymocyte precursors proliferate in response to interleukin-7 but have lost myeloid differentiation potential,” Blood, vol. 82, no. 12, pp. 3675–3685, 1993. View at Scopus
  14. I. Visan, J. S. Yuan, J. B. Tan, K. Cretegny, and C. J. Guidos, “Regulation of intrathymic T-cell development by lunatic fringe- Notch1 interactions,” Immunological Reviews, vol. 209, pp. 76–94, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. I. Visan, J. S. Yuan, Y. Liu, P. Stanley, and C. J. Guidos, “Lunatic Fringe enhances competition for Delta-like Notch ligands but does not overcome defective pre-TCR signaling during thymocyte β-selection in vivo,” Journal of Immunology, vol. 185, no. 8, pp. 4609–4617, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. P. P. Roozen, M. H. Brugman, and F. J. Staal, “Differential requirements for Wnt and Notch signaling in hematopoietic versus thymic niches,” Annals of the New York Academy of Sciences, vol. 1266, pp. 78–93, 2012. View at Publisher · View at Google Scholar
  17. I. van de Walle, E. Waegemans, J. de Medts et al., “Specific Notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength,” Journal of Experimental Medicine, vol. 210, no. 4, pp. 683–697, 2013. View at Publisher · View at Google Scholar
  18. P. E. Love and A. Bhandoola, “Signal integration and crosstalk during thymocyte migration and emigration,” Nature Reviews Immunology, vol. 11, no. 7, pp. 469–477, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. V. C. Seitan, B. Hao, K. Tachibana-Konwalski et al., “A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation,” Nature, vol. 476, no. 7361, pp. 467–471, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. D. A. Witherden and W. L. Havran, “Molecular aspects of epithelial γδ T cell regulation,” Trends in Immunology, vol. 32, no. 6, pp. 265–271, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. L. Klein and K. Jovanovic, “Regulatory T cell lineage commitment in the thymus,” Seminars in Immunology, vol. 23, no. 6, pp. 401–409, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. J. M. Coquet, J. C. Ribot, N. Babala et al., “Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway,” Journal of Experimental Medicine, vol. 210, no. 4, pp. 715–728, 2013. View at Publisher · View at Google Scholar
  23. D. I. Godfrey and S. P. Berzins, “Control points in NKT-cell development,” Nature Reviews Immunology, vol. 7, no. 7, pp. 505–518, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. J. Banchereau, F. Briere, C. Caux et al., “Immunobiology of dendritic cells,” Annual Review of Immunology, vol. 18, pp. 767–811, 2000. View at Publisher · View at Google Scholar · View at Scopus
  25. N. Garbi and T. Kreutzberg, “Dendritic cells enhance the antigen sensitivity of T cells,” Frontiers in Immunology, vol. 3, article 389, 2012.
  26. S. C. Knight, B. A. Askonas, and S. E. Macatonia, “Dendritic cells as targets for cytotoxic T lymphocytes,” Advances in Experimental Medicine and Biology, vol. 417, pp. 389–394, 1997. View at Scopus
  27. R. A. Willis, J. W. Kappler, and P. C. Marrack, “CD8 T cell competition for dendritic cells in vivo is an early event in activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 32, pp. 12063–12068, 2006. View at Publisher · View at Google Scholar · View at Scopus
  28. J. C. Howard and D. B. Wilson, “Specific positive selection of lymphocytes reactive to strong histocompatibility antigens,” Journal of Experimental Medicine, vol. 140, no. 3, pp. 660–672, 1974. View at Scopus
  29. B. A. Kyewski, C. G. Fathman, and H. S. Kaplan, “Intrathymic presentation of circulating non-major histocompatibility complex antigens,” Nature, vol. 308, no. 5955, pp. 196–199, 1984. View at Scopus
  30. S. M. Hedrick, “Positive selection in the thymus: an enigma wrapped in a mystery,” Journal of Immunology, vol. 188, no. 5, pp. 2043–2045, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. Y. Zilberman, E. Yefenof, S. Katzav, A. Dorogin, N. Rosenheimer-Goudsmid, and R. Guy, “Apoptosis of thymic lymphoma clones by thymic epithelial cells: a putative model for ‘death by neglect’,” Immunology Letters, vol. 67, no. 2, pp. 95–104, 1999. View at Publisher · View at Google Scholar · View at Scopus
  32. O. Cohen, E. Ish-Shalom, S. Kfir-Erenfeld, I. Herr, and E. Yefenof, “Nitric oxide and glucocorticoids synergize in inducing apoptosis of CD4+8+ thymocytes: implications for “death by neglect” and T-cell function,” International Immunology, vol. 24, no. 12, pp. 783–791, 2012. View at Publisher · View at Google Scholar
  33. H. Hengartner, B. Odermat, R. Schneider et al., “Deletion of self-reactive T cells before entry into the thymus medulla,” Nature, vol. 336, no. 6197, pp. 388–390, 1988. View at Scopus
  34. Y. Takahama, “T lymphocyte development and selection in the thymic microenvironments,” Nature Reviews Immunology, vol. 84, no. 3, pp. 177–1782, 2012.
  35. C. J. Guidos, J. S. Danska, C. G. Fathman, and I. L. Weissman, “T cell receptor-mediated negative selection of autoreactive T lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages,” Journal of Experimental Medicine, vol. 172, no. 3, pp. 835–845, 1990. View at Publisher · View at Google Scholar · View at Scopus
  36. E. Fiorini, I. Ferrero, E. Merck et al., “Cutting edge: thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells,” Journal of Immunology, vol. 181, no. 12, pp. 8199–8203, 2008. View at Scopus
  37. M. L. Allende, J. L. Dreier, S. Mandala, and R. L. Proia, “Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration,” The Journal of Biological Chemistry, vol. 279, no. 15, pp. 15396–15401, 2004. View at Publisher · View at Google Scholar · View at Scopus
  38. Y. Maeda, N. Seki, N. Sato, K. Sugahara, and K. Chiba, “Sphingosine 1-phosphate receptor type 1 regulates egress of mature T cells from mouse bone marrow,” International Immunology, vol. 22, no. 6, pp. 515–525, 2010. View at Publisher · View at Google Scholar · View at Scopus
  39. M. A. Ritter and D. B. Palmer, “The human thymic microenvironment: new approaches to functional analysis,” Seminars in Immunology, vol. 11, no. 1, pp. 13–21, 1999. View at Publisher · View at Google Scholar · View at Scopus
  40. N. R. Manley, E. R. Richie, C. C. Blackburn, B. G. Condie, and J. Sage, “Structure and function of the thymic microenvironment,” Frontiers in Bioscience, vol. 16, no. 7, pp. 2461–2477, 2011. View at Publisher · View at Google Scholar · View at Scopus
  41. K. Hirokawa and T. Makinodan, “Thymic involution: effect on T cell differentiation,” Journal of Immunology, vol. 114, no. 6, pp. 1659–1664, 1975. View at Scopus
  42. L. Henry and G. Anderson, “Epithelial-cell architecture during involution of the human thymus,” Journal of Pathology, vol. 152, no. 3, pp. 149–155, 1987. View at Scopus
  43. N. Yajima, K. Sakamaki, and S. Yonehara, “Age-related thymic involution is mediated by Fas on thymic epithelial cells,” International Immunology, vol. 16, no. 7, pp. 1027–1035, 2004. View at Publisher · View at Google Scholar · View at Scopus
  44. G. Anderson and Y. Takahama, “Thymic epithelial cells: working class heroes for T cell development and repertoire selection,” Trends in Immunology, vol. 33, no. 6, pp. 256–263, 2012. View at Publisher · View at Google Scholar
  45. S. R. Wellhausen and D. L. Boros, “Atrophy of the thymic cortex in mice with granulomatous Schistosomiasis mansoni,” Infection and Immunity, vol. 35, no. 3, pp. 1063–1069, 1982. View at Scopus
  46. P. G. Auwaerter, H. Kaneshima, J. M. McCune, G. Wiegand, and D. E. Griffin, “Measles virus infection of thymic epithelium in the SCID-hu mouse leads to thymocyte apoptosis,” Journal of Virology, vol. 70, no. 6, pp. 3734–3740, 1996. View at Scopus
  47. P. C. S. Souto, V. N. Brito, J. Gameiro, M. A. da Cruz-Höfling, and L. Verinaud, “Programmed cell death in thymus during experimental paracoccidioidomycosis,” Medical Microbiology and Immunology, vol. 192, no. 4, pp. 225–229, 2003. View at Publisher · View at Google Scholar · View at Scopus
  48. V. N. Brito, P. C. S. Souto, M. A. Cruz-Höfling, L. C. Ricci, and L. Verinaud, “Thymus invasion and atrophy induced by Paracoccidioides brasiliensis in BALB/c mice,” Medical Mycology, vol. 41, no. 2, pp. 83–87, 2003. View at Scopus
  49. W. Chen, R. Kuolee, J. W. Austin, H. Shen, Y. Che, and J. W. Conlan, “Low dose aerosol infection of mice with virulent type A Francisella tularensis induces severe thymus atrophy and CD4+CD8+ thymocyte depletion,” Microbial Pathogenesis, vol. 39, no. 5-6, pp. 189–196, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. W. Savino, “The thymus is a common target organ in infectious diseases,” PLoS Pathogens, vol. 2, no. 6, article e62, 2006. View at Publisher · View at Google Scholar · View at Scopus
  51. J. Gameiro, P. R. A. Nagib, C. F. Andrade et al., “Changes in cell migration-related molecules expressed by thymic microenvironment during experimental Plasmodium berghei infection: consequences on thymocyte development,” Immunology, vol. 129, no. 2, pp. 248–256, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. C. Francelin, L. C. Paulino, J. Gameiro, and L. Verinaud, “Effects of Plasmodium berghei on thymus: high levels of apoptosis and premature egress of CD4+CD8+ thymocytes in experimentally infected mice,” Immunobiology, vol. 216, no. 10, pp. 1148–1154, 2011. View at Publisher · View at Google Scholar · View at Scopus
  53. A. Morrot, J. B. de Albuquerque, L. R. Berbert, C. E. de Carvalho Pinto, J. de Meis, and W. Savino, “Dynamics of lymphocyte populations during Trypanosoma cruzi infection: from thymocyte depletion to differential cell expansion/contraction in peripheral lymphoid organs,” Journal of Tropical Medicine, vol. 2012, Article ID 747185, 7 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  54. L. Verinaud, M. A. da Cruz-Höfling, J. K. Sakurada et al., “Immunodepression induced by Trypanosoma cruzi and mouse hepatitis virus type 3 is associated with thymus apoptosis,” Clinical and Diagnostic Laboratory Immunology, vol. 5, no. 2, pp. 186–191, 1998. View at Scopus
  55. J. de Meis, D. A. Farias-de-Oliveira, P. H. N. Panzenhagen et al., “Thymus atrophy and double-positive escape are common features in infectious diseases,” Journal of Parasitology Research, vol. 2012, Article ID 574020, 9 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  56. M. D. C. L. de Moraes, P. Minoprio, M. Dy, M. Dardenne, W. Savino, and M. Hontebeyrie-Joskowicz, “Endogenous IL-10 and IFN-γ production controls thymic cell proliferation in mice acutely infected by Trypanosoma cruzi,” Scandinavian Journal of Immunology, vol. 39, no. 1, pp. 51–58, 1994. View at Publisher · View at Google Scholar · View at Scopus
  57. B. M. Greene and D. G. Colley, “Eosinophils and immune mechanisms. III. Production of the lymphokine eosinophil stimulation promotor by mouse T lymphocytes,” Journal of Immunology, vol. 116, no. 4, pp. 1078–1083, 1976. View at Scopus
  58. A. Henriques-Pons, J. DeMeis, V. Cotta-de-Almeida, W. Savino, and T. C. Araújo-Jorge, “Fas and perforin are not required for thymus atrophy induced by Trypanosoma cruzi infection,” Experimental Parasitology, vol. 107, no. 1-2, pp. 1–4, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. E. Roggero, A. R. Pérez, O. A. Bottasso, H. O. Besedovsky, and A. del Rey, “Neuroendocrine-immunology of experimental Chagas' disease,” Annals of the New York Academy of Sciences, vol. 1153, pp. 264–271, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. L. J. M. Carvalho, M. F. Ferreira-da-Cruz, C. T. Daniel-Ribeiro, M. Pelajo-Machado, and H. L. Lenzi, “Plasmodium berghei ANKA infection induces thymocyte apoptosis and thymocyte depletion in CBA mice,” Memórias do Instituto Oswaldo Cruz, vol. 101, no. 5, pp. 523–528, 2006. View at Scopus
  61. M. C. L. de Moraes, M. Hontebeyrie-Joskowicz, F. Leboulenger, W. Savino, M. Dardenne, and F. Lepault, “Studies on the thymus in Chagas' disease. II. Thymocyte subset fluctuations in Trypanosoma cruzi-infected mice: relationship to stress,” Scandinavian Journal of Immunology, vol. 33, no. 3, pp. 267–275, 1991. View at Scopus
  62. V. N. Ivanov and J. Nikolić-Žugić, “Biochemical and kinetic characterization of the glucocorticoid-induced apoptosis of immature CD4+CD8+ thymocytes,” International Immunology, vol. 10, no. 12, pp. 1807–1817, 1998. View at Scopus
  63. E. Corrêa-De-Santana, M. Paez-Pereda, M. Theodoropoulou et al., “Hypothalamus-pituitary-adrenal axis during Trypanosoma cruzi acute infection in mice,” Journal of Neuroimmunology, vol. 173, no. 1-2, pp. 12–22, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Lepletier, C. V. de Frias, A. Morrot, and W. Savino, “Thymic atrophy in acute experimental Chagas disease is associated with an imbalance of stress hormones,” Annals of the New York Academy of Sciences, vol. 1262, no. 1, pp. 45–50, 2012. View at Publisher · View at Google Scholar
  65. C. S. Rosenberg, D. L. Martin, and R. L. Tarleton, “CD8+ T cells specific for immunodominant trans-sialidase epitopes contribute to control of Trypanosoma cruzi infection but are not required for resistance,” Journal of Immunology, vol. 185, no. 1, pp. 560–568, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. G. A. Rabinovich, L. G. Baum, N. Tinari et al., “Galectins and their ligands: amplifiers, silencers or tuners of the inflammatory response?” Trends in Immunology, vol. 23, no. 6, pp. 313–320, 2002. View at Publisher · View at Google Scholar · View at Scopus
  67. W. Savino, D. A. Mendes-da-Cruz, S. Smaniotto, E. Silva-Monteiro, and D. M. S. Villa-Verde, “Molecular mechanisms governing thymocyte migration: combined role of chemokines and extracellular matrix,” Journal of Leukocyte Biology, vol. 75, no. 6, pp. 951–961, 2004. View at Publisher · View at Google Scholar · View at Scopus
  68. B. N. Stillman, D. K. Hsu, M. Pang et al., “Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death,” Journal of Immunology, vol. 176, no. 2, pp. 778–789, 2006. View at Scopus
  69. E. Silva-Monteiro, L. R. Lorenzato, O. K. Nihei et al., “Altered expression of galectin-3 induces cortical thymocyte depletion and premature exit of immature thymocytes during Trypanosoma cruzi infection,” The American Journal of Pathology, vol. 170, no. 2, pp. 546–556, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Mantuano-Barradas, A. Henriques-Pons, T. C. Araújo-Jorge, F. Di Virgilio, R. Coutinho-Silva, and P. M. Persechini, “Extracellular ATP induces cell death in CD4+/CD8+ double-positive thymocytes in mice infected with Trypanosoma cruzi,” Microbes and Infection, vol. 5, no. 15, pp. 1363–1371, 2003. View at Publisher · View at Google Scholar · View at Scopus
  71. W. Savino, M. D. C. L. de Moraes, M. Hontebeyrie-Joskowicz, and M. Dardenne, “Studies on the thymus in Chagas' disease. I. Changes in the thymic microenvironment in mice acutely infected with Trypanosoma cruzi,” European Journal of Immunology, vol. 19, no. 9, pp. 1727–1733, 1989. View at Scopus
  72. V. Cotta-de-Almeida, A. Bonomo, D. A. Mendes-da-Cruz et al., “Trypanosoma cruzi infection modulates intrathymic contents of extracellular matrix ligands and receptors and alters thymocyte migration,” European Journal of Immunology, vol. 33, no. 9, pp. 2439–2448, 2003. View at Publisher · View at Google Scholar · View at Scopus
  73. E. Roggero, A. R. Pérez, M. Tamae-Kakazu et al., “Edogenous glucocorticoids cause thymus atrophy but are protective during acute Trypanosoma cruzi infection,” Journal of Endocrinology, vol. 190, no. 2, pp. 495–503, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. A. R. Pérez, E. Roggero, A. Nicora et al., “Thymus atrophy during Trypanosoma cruzi infection is caused by an immuno-endocrine imbalance,” Brain, Behavior, and Immunity, vol. 21, no. 7, pp. 890–900, 2007. View at Publisher · View at Google Scholar · View at Scopus
  75. S. Schenkman, M. Jiang, G. W. Hart, and V. Nussenzweig, “A novel cell surface trans-sialidase of Trypanosoma cruzi generates a stage-specific epitope required for invasion of mammalian cells,” Cell, vol. 65, no. 7, pp. 1117–1125, 1991. View at Scopus
  76. S. Schenkman, L. P. de Carvalho, and V. Nussenzweig, “Trypanosoma cruzi trans-sialidase and neuraminidase activities can be mediated by the same enzymes,” Journal of Experimental Medicine, vol. 175, no. 2, pp. 567–575, 1992. View at Scopus
  77. S. S. Dc-Rubin and S. Schenkman, “Trypanosoma cruzi trans-sialidase as a multifunctional enzyme in Chagas' disease,” Cellular Microbiology, vol. 14, no. 10, pp. 1522–1530, 2012. View at Publisher · View at Google Scholar
  78. D. H. Gray, F. Kupresanin, S. P. Berzins et al., “The BH3-only proteins Bim and Puma cooperate to impose deletional tolerance of organ-specific antigens,” Immunity, vol. 37, no. 3, pp. 451–462, 2012. View at Publisher · View at Google Scholar
  79. J. Sprent and H. Kishimoto, “The thymus and negative selection,” Immunological Reviews, vol. 185, pp. 126–135, 2002. View at Publisher · View at Google Scholar · View at Scopus
  80. N. M. Milićević and Z. Milićević, “Thymus cell-cell interactions,” International Review of Cytology, vol. 235, pp. 1–52, 2004. View at Publisher · View at Google Scholar · View at Scopus
  81. N. M. Milićević and Z. Milićević, “Ultrastructural identification of specialized endocytic compartments in macrophages of the thymic cortico-medullary zone and germinal centers of peripheral lymphatic organs of the rat,” Annals of Anatomy, vol. 182, no. 5, pp. 471–478, 2000. View at Scopus
  82. A. Morrot, E. Terra-Granado, A. R. Pérez et al., “Chagasic thymic atrophy does not affect negative selection but results in the export of activated CD4+CD8+ T cells in severe forms of human disease,” PLoS Neglected Tropical Diseases, vol. 5, no. 8, Article ID e1268, 2011. View at Publisher · View at Google Scholar · View at Scopus
  83. E. Fiorini, P. C. Marchisio, M. T. Scupoli et al., “Adhesion of immature and mature T cells induces in human thymic epithelial cells (TEC) activation of IL-6 gene trascription factors (NF-κB and NF-IL6) and IL-6 gene expression: Role of α3β1 and α6β4 integrins,” Developmental Immunology, vol. 7, no. 2–4, pp. 195–208, 2000. View at Scopus
  84. T. Cejalvo, J. J. Munoz, E. Tobajas et al., “Ephrin-B-dependent thymic epithelial cell-thymocyte interactions are necessary for correct T cell differentiation and thymus histology organization: relevance for thymic cortex development,” Journal of Immunology, vol. 190, no. 6, pp. 2670–2681, 2013. View at Publisher · View at Google Scholar
  85. G. A. Hollander, B. Wang, A. Nichogiannopoulou et al., “Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes,” Nature, vol. 373, no. 6512, pp. 350–353, 1995. View at Scopus
  86. S. Zuklys, G. Balciunaite, A. Agarwal, E. Fasler-Kan, E. Palmer, and G. A. Hollander, “Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED),” Journal of Immunology, vol. 165, no. 4, pp. 1976–1983, 2000. View at Scopus
  87. P. Peterson, T. Org, and A. Rebane, “Transcriptional regulation by AIRE: molecular mechanisms of central tolerance,” Nature Reviews Immunology, vol. 8, no. 12, pp. 948–957, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. M. Zhu, R. K. Chin, P. A. Christiansen et al., “NF-κB2 is required for the establishment of central tolerance through an Aire-dependent pathway,” Journal of Clinical Investigation, vol. 116, no. 11, pp. 2964–2971, 2006. View at Publisher · View at Google Scholar · View at Scopus
  89. R. T. Taniguchi and M. S. Anderson, “The role of Aire in clonal selection,” Immunology and Cell Biology, vol. 89, no. 1, pp. 40–44, 2011. View at Publisher · View at Google Scholar · View at Scopus
  90. M. C. L. de Moraes, M. Hontebeyrie-Joskowicz, M. Dardenne, and W. Savino, “Modulation of thymocyte subsets during acute and chronic phases of experimental Trypanosoma cruzi infection,” Immunology, vol. 77, no. 1, pp. 95–98, 1992. View at Scopus
  91. X. Liu, S. Dai, Y. Zhu, P. Marrack, and J. W. Kappler, “The structure of a Bcl-xL/Bim fragment complex: implications for Bim function,” Immunity, vol. 19, no. 3, pp. 341–352, 2003. View at Publisher · View at Google Scholar · View at Scopus
  92. S. Schenkman, M. A. J. Ferguson, N. Heise, M. L. C. de Almeida, R. A. Mortara, and N. Yoshida, “Mucin-like glycoproteins linked to the membrane by glycosylphosphatidylinositol anchor are the major acceptors of sialic acid in a reaction catalyzed by trans-sialidase in metacyclic forms of Trypanosoma cruzi,” Molecular and Biochemical Parasitology, vol. 59, no. 2, pp. 293–303, 1993. View at Publisher · View at Google Scholar · View at Scopus
  93. A. R. Todeschini, W. B. Dias, M. F. Girard, J. Wieruszeski, L. Mendonça-Previato, and J. O. Previato, “Enzymatically inactive trans-sialidase from Trypanosoma cruzi binds sialyl and β-galactopyranosyl residues in a sequential ordered mechanism,” The Journal of Biological Chemistry, vol. 279, no. 7, pp. 5323–5328, 2004. View at Publisher · View at Google Scholar · View at Scopus
  94. M. S. Leguizamon, O. E. Campetella, S. M. G. Cappa, and A. C. C. Frasch, “Mice infected with Trypanosoma cruzi produce antibodies against the enzymatic domain of trans-sialidase that inhibit its activity,” Infection and Immunity, vol. 62, no. 8, pp. 3441–3446, 1994. View at Scopus
  95. J. Mucci, E. Mocetti, M. S. Leguizamón, and O. Campetella, “A sexual dimorphism in intrathymic sialylation survey is revealed by the trans-sialidase from Trypanosoma cruzi,” Journal of Immunology, vol. 174, no. 8, pp. 4545–4550, 2005. View at Scopus
  96. J. Mucci, A. Hidalgo, E. Mocetti, P. F. Argibay, M. S. Leguizamón, and O. Campetella, “Thymocyte depletion in Trypanosoma cruzi infection is mediated by trans-sialidase-induced apoptosis on nurse cells complex,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 6, pp. 3896–3901, 2002. View at Publisher · View at Google Scholar · View at Scopus
  97. R. P. Muiá, H. Yu, J. A. Prescher et al., “Identification of glycoproteins targeted by Trypanosoma cruzi trans-sialidase, a virulence factor that disturbs lymphocyte glycosylation,” Glycobiology, vol. 20, no. 7, pp. 833–842, 2010. View at Publisher · View at Google Scholar · View at Scopus
  98. A. F. Nardy, J. L. da Silva Filho, A. R. Pérez et al., “Trans-sialidase from Trypanosoma cruzi enhances the adhesion properties and fibronectin-driven migration of thymocytes,” Microbes and Infection, vol. 15, no. 5, pp. 365–374, 2013. View at Publisher · View at Google Scholar
  99. S. C. da Costa, K. S. Calabrese, P. G. Bauer, W. Savino, and P. H. Lagrange, “Studies of the thymus in Chagas' disease: III. Colonization of the thymus and other lymphoid organs of adult and newborn mice by Trypanosoma cruzi,” Pathologie Biologie, vol. 39, no. 2, pp. 91–97, 1991. View at Scopus
  100. K. Utsumi, M. Sawada, S. Narumiya et al., “Adhesion of immature thymocytes to thymic stromal cells through fibronectin molecules and its significance for the induction of thymocyte differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 13, pp. 5685–5689, 1991. View at Publisher · View at Google Scholar · View at Scopus
  101. W. Savino, D. A. Mendes-da-Cruz, J. S. Silva, M. Dardenne, and V. Cotta-de-Almeida, “Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines?” Trends in Immunology, vol. 23, no. 6, pp. 305–313, 2002. View at Publisher · View at Google Scholar · View at Scopus
  102. W. Gillespie, J. C. Paulson, S. Kelm, M. Pang, and L. G. Baum, “Regulation of α2,3-sialyltransferase expression correlates with conversion of peanut agglutinin (PNA)+ to PNA- phenotype in developing thymocytes,” The Journal of Biological Chemistry, vol. 268, no. 6, pp. 3801–3804, 1993. View at Scopus
  103. L. Linhares-Lacerda, M. Ribeiro-Alves, A. C. M. D. A. Nogueira et al., “RNA interference-mediated knockdown of CD49e (α5 integrin chain) in human thymic epithelial cells modulates the expression of multiple genes and decreases thymocyte adhesion,” BMC Genomics, vol. 11, supplement 5, article S2, 2010. View at Publisher · View at Google Scholar · View at Scopus
  104. I. M. Otto, T. Raabe, U. E. E. Rennefahrt, P. Bork, U. R. Rapp, and E. Kerkhoff, “The p150-Spir protein provides a link between c-Jun N-terminal kinase function and actin reorganization,” Current Biology, vol. 10, no. 6, pp. 345–348, 2000. View at Publisher · View at Google Scholar · View at Scopus
  105. D. A. Mendes-da-Cruz, J. de Meis, V. Cotta-de-Almeida, and W. Savino, “Experimental Trypanosoma cruzi infection alters the shaping of the central and peripheral T-cell repertoire,” Microbes and Infection, vol. 5, no. 10, pp. 825–832, 2003. View at Publisher · View at Google Scholar · View at Scopus
  106. N. A. Giraldo, N. I. Bolaños, A. Cuellar et al., “Increased CD4+/CD8+ double-positive T cells in chronic chagasic patients,” PLoS Neglected Tropical Diseases, vol. 5, no. 8, Article ID e1294, 2011. View at Publisher · View at Google Scholar · View at Scopus
  107. S. D. Rosen, “Ligands for L-selectin: homing, inflammation, and beyond,” Annual Review of Immunology, vol. 22, pp. 129–156, 2004. View at Publisher · View at Google Scholar · View at Scopus
  108. K. Nam, H. Akari, K. Terao, H. Shibata, S. Kawamura, and Y. Yoshikawa, “Peripheral blood extrathymic CD4+ CD8+ T cells with high cytotoxic activity are from the same lineage as CD4+ CD8- T cells in cynomolgus monkeys,” International Immunology, vol. 12, no. 7, pp. 1095–1103, 2000. View at Scopus
  109. M. Nascimbeni, E. Shin, L. Chiriboga, D. E. Kleiner, and B. Rehermann, “Peripheral CD4+CD8+ T cells are differentiated effector memory cells with antiviral functions,” Blood, vol. 104, no. 2, pp. 478–486, 2004. View at Publisher · View at Google Scholar · View at Scopus
  110. H. Akari, K. Terao, Y. Murayama, K. Nam, and Y. Yoshikawa, “Peripheral blood CD4+CD8+ lymphocytes in cynomolgus monkeys are of resting memory T lineage,” International Immunology, vol. 9, no. 4, pp. 591–597, 1997. View at Publisher · View at Google Scholar · View at Scopus
  111. H. Akari, K. Nam, K. Mori et al., “Effects of SIVmac infection on peripheral blood CD4+CD8+ T lymphocytes in cynomolgus macaques,” Clinical Immunology, vol. 91, no. 3, pp. 321–329, 1999. View at Publisher · View at Google Scholar · View at Scopus
  112. L. Lamontagne, E. Massicotte, and C. Page, “Mouse hepatitis viral infection induces an extrathymic differentiation of the specific intrahepatic αβ-TCR(intermediate) LFA-1(high) T-cell population,” Immunology, vol. 90, no. 3, pp. 402–411, 1997. View at Scopus
  113. M. Nascimbeni, S. Pol, and B. Saunier, “Distinct CD4+CD8+ double-positive T cells in the blood and liver of patients during chronic hepatitis B and C,” PLoS ONE, vol. 6, no. 5, Article ID e20145, 2011. View at Publisher · View at Google Scholar · View at Scopus
  114. L. Weiss, A. Roux, S. Garcia et al., “Persistent expansion, in a human immunodeficiency virus-infected person, of Vβ-restricted CD4+CD8+ T lymphocytes that express cytotoxicity-associated molecules and are committed to produce interferon-γ and tumor necrosis factor-α,” Journal of Infectious Diseases, vol. 178, no. 4, pp. 1158–1162, 1998. View at Scopus
  115. M. A. Suni, S. A. Ghanekar, D. W. Houck et al., “CD4+CD8dim T lymphocyte exhit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens,” European Journal of Immunology, vol. 31, no. 8, pp. 2512–2520, 2001. View at Publisher · View at Google Scholar
  116. A. Zloza, Y. B. Sullivan, E. Connick, A. L. Landay, and L. Al-Harthi, “CD8+ T cells that express CD4 on their surface (CD4 dimCD8bright T cells) recognize an antigen-specific target, are detected in vivo, and can be productively infected by T-tropic HIV,” Blood, vol. 102, no. 6, pp. 2156–2164, 2003. View at Publisher · View at Google Scholar · View at Scopus
  117. R. Howe, S. Dillon, L. Rogers et al., “Phenotypic and functional characterization of HIV-1-specific CD4+CD8+ double-positive T cells in early and chronic HIV-1 infection,” Journal of Acquired Immune Deficiency Syndromes, vol. 50, no. 5, pp. 444–456, 2009. View at Publisher · View at Google Scholar · View at Scopus
  118. N. K. Chauhan, M. Vajpayee, K. Mojumdar, R. Singh, and A. Singh, “Study of CD4+CD8+ double positive T-lymphocyte phenotype and function in Indian patients infected with HIV-1,” Journal of Medical Virology, vol. 84, no. 6, pp. 845–856, 2012. View at Publisher · View at Google Scholar · View at Scopus
  119. M. A. Frahm, R. A. Picking, J. D. Kuruc et al., “CD4+CD8+ T cells represent a significant portion of the anti-HIV T cell response to acute HIV infection,” Journal of Immunology, vol. 188, no. 9, pp. 4289–4296, 2012. View at Publisher · View at Google Scholar · View at Scopus
  120. L. D. Barber and P. Parham, “Peptide binding to major histocompatibility complex molecules,” Annual Review of Cell Biology, vol. 9, pp. 163–206, 1993. View at Scopus
  121. R. Brink, T. G. Phan, D. Paus, and T. D. Chan, “Visualizing the effects of antigen affinity on T-dependent B-cell differentiation,” Immunology and Cell Biology, vol. 86, no. 1, pp. 31–39, 2008. View at Publisher · View at Google Scholar · View at Scopus
  122. J. Hernández, Y. Garfias, A. Nieto, C. Mercado, L. F. Montaño, and E. Zenteno, “Comparative evaluation of the CD4+CD8+ and CD4+CD8- lymphocytes in the immune response to porcine rubulavirus,” Veterinary Immunology and Immunopathology, vol. 79, no. 3-4, pp. 249–259, 2001. View at Publisher · View at Google Scholar · View at Scopus
  123. P. Hillemeyer, M. D. White, and D. W. Pascual, “Development of a transient CD4+CD8+ T cell subset in the cervical lymph nodes following intratracheal instillation with an adenovirus vector,” Cellular Immunology, vol. 215, no. 2, pp. 173–185, 2002. View at Publisher · View at Google Scholar · View at Scopus
  124. S. Raza, S. Naik, V. P. Kancharla, F. Tafera, and M. R. Kalavar, “Dual-positive (CD4+/CD8+) acute adult T-cell leukemia/lymphoma associated with complex karyotype and refractory hypercalcemia: case report and literature review,” Case Reports in Oncology, vol. 3, no. 3, pp. 489–494, 2010. View at Publisher · View at Google Scholar · View at Scopus
  125. D. Bismarck, N. Schütze, P. Moore, M. Büttner, G. Alber, and H. V. Buttlar, “Canine CD4+CD8+ double positive T cells in peripheral blood have features of activated T cells,” Veterinary Immunology and Immunopathology, vol. 149, no. 3-4, pp. 157–166, 2012. View at Publisher · View at Google Scholar
  126. B. T. Ober, A. Summerfield, C. Mattlinger et al., “Vaccine-induced, pseudorabies virus-specific, extrathymic CD4+CD8+ memory T-helper cells in swine,” Journal of Virology, vol. 72, no. 6, pp. 4866–4873, 1998. View at Scopus
  127. T. G. M. de Bruin, E. M. A. van Rooij, Y. E. de Visser, and A. T. J. Bianchi, “Cytolytic function for pseudorabies virus-stimulated porcine CD4+CD8dull+ lymphocytes,” Viral Immunology, vol. 13, no. 4, pp. 511–520, 2000. View at Scopus
  128. V. Dwivedi, C. Manickam, R. Patterson et al., “Cross-protective immunity to porcine reproductive and respiratory syndrome virus by intranasal delivery of a live virus vaccine with a potent adjuvant,” Vaccine, vol. 29, no. 23, pp. 4058–4066, 2011. View at Publisher · View at Google Scholar · View at Scopus
  129. Y. Parel and C. Chizzolini, “CD4+ CD8+ double positive (DP) T cells in health and disease,” Autoimmunity Reviews, vol. 3, no. 3, pp. 215–220, 2004. View at Publisher · View at Google Scholar · View at Scopus
  130. S. G. Kitchen, Y. D. Korin, M. D. Roth, A. Landay, and J. A. Zack, “Costimulation of naive CD8+ lymphocytes induces CD4 expression and allows human immunodeficiency virus type 1 infection,” Journal of Virology, vol. 72, no. 11, pp. 9054–9060, 1998. View at Scopus
  131. G. J. Hughes, A. Cochrane, C. Leen, S. Morris, J. E. Bell, and P. Simmonds, “HIV-1-infected CD8+CD4+ T cells decay in vivo at a similar rate to infected CD4 T cells during HAART,” AIDS, vol. 22, no. 1, pp. 57–65, 2008. View at Publisher · View at Google Scholar · View at Scopus
  132. J. J. Mattapallil, E. Reay, and S. Dandekar, “An early expansion of CD8αβ T cells, but depletion of resident CD8αα T cells, occurs in the intestinal epithelium during primary simian immunodeficiency virus infection,” AIDS, vol. 14, no. 6, pp. 637–646, 2000. View at Publisher · View at Google Scholar · View at Scopus
  133. R. S. Veazey, K. G. Mansfield, I. C. Tham et al., “Dynamics of CCR5 expression by CD4+ T cells in lymphoid tissues during simian immunodeficiency virus infection,” Journal of Virology, vol. 74, no. 23, pp. 11001–11007, 2000. View at Publisher · View at Google Scholar · View at Scopus
  134. V. M. Hirsch, “What can natural infection of African monkeys with simian immunodeficiency virus tell us about the pathogenesis of AIDS?” AIDS Reviews, vol. 6, no. 1, pp. 40–53, 2004. View at Scopus
  135. J. W. Mellors, C. R. Rinaldo Jr., P. Gupta, R. M. White, J. A. Todd, and L. A. Kingsley, “Prognosis in HIV-1 infection predicted by the quantity of virus in plasma,” Science, vol. 272, no. 5265, pp. 1167–1170, 1996. View at Scopus
  136. R. Gautam, T. Gaufin, I. Butler et al., “Simian immunodeficiency virus SIVrcm, a unique CCR2-tropic virus, selectively depletes memory CD4+ T cells in pigtailed macaques through expanded coreceptor usage in vivo,” Journal of Virology, vol. 83, no. 16, pp. 7894–7908, 2009. View at Publisher · View at Google Scholar · View at Scopus
  137. V. Ribrag, D. Salmon, F. Picard, M. Guesnu, D. Sicard, and F. Dreyfus, “Increase in double-positive CD4+CD8+ peripheral T-cell subsets in an HIV-infected patient,” AIDS, vol. 7, no. 11, article 1530, 1993. View at Scopus
  138. G. F. Ferraccioli, E. Tonutti, L. Casatta et al., “CD4 cytopenia and occasional expansion of CD4+CD8+ lymphocytes in Sjogren's syndrome,” Clinical and Experimental Rheumatology, vol. 14, no. 2, pp. 125–130, 1996. View at Scopus
  139. J. Hirao and K. Sugita, “Circulating CD4+CD8+ T lymphocytes in patients with Kawasaki disease,” Clinical and Experimental Immunology, vol. 111, no. 2, pp. 397–401, 1998. View at Publisher · View at Google Scholar · View at Scopus