Dynamics of Lymphocyte Populations during Trypanosoma cruzi Infection: From Thymocyte Depletion to Differential Cell Expansion/Contraction in Peripheral Lymphoid Organs
The comprehension of the immune responses in infectious diseases is crucial for developing novel therapeutic strategies. Here, we review current findings on the dynamics of lymphocyte subpopulations following experimental acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. In the thymus, although the negative selection process of the T-cell repertoire remains operational, there is a massive thymocyte depletion and abnormal release of immature CD4+CD8+ cells to peripheral lymphoid organs, where they acquire an activated phenotype similar to activated effector or memory T cells. These cells apparently bypassed the negative selection process, and some of them are potentially autoimmune. In infected animals, an atrophy of mesenteric lymph nodes is also observed, in contrast with the lymphocyte expansion in spleen and subcutaneous lymph nodes, illustrating a complex and organ specific dynamics of lymphocyte subpopulations. Accordingly, T- and B-cell activation is seen in subcutaneous lymph nodes and spleen, but not in mesenteric lymph nodes. Lastly, although the function of peripheral CD4+CD8+ T-cell population remains to be defined in vivo, their presence may contribute to the immunopathological events found in both murine and human Chagas disease. 1. Introduction Trypanosoma cruzi is the causative agent of Chagas disease affecting more than 10 million people in Latin America. The parasite is transmitted by feces of infected insect vectors belonging to the family Reduviidae [1–3]. After infection, the initial acute phase of the disease progresses to an asymptomatic indeterminate period with virtually undetectable parasitemia and a strong humoral and cellular anti-T. cruzi responses. Up to several years after the initial infection, approximately 20 to 30% of all infected individuals develop a chronic inflammatory disease primarily affecting the heart [2–4]. Although different mechanisms have been proposed to trigger this pathology, there is a growing body of evidence that parasite persistence is associated with a chronic inflammatory response, which is the primary cause of Chagas disease [5, 6]. Experimental models of T. cruzi infection have been widely used to study various aspects of the infection. Acute infection in mice leads to strong activation of innate and adaptive immune response [7, 8]. In the course of infection, there is a fine change in the dynamics on the size of lymphocyte populations that contributes to regional specificities of the immune response in central and peripheral lymphoid organs: while there is an expansion
References
[1]
E. R. Parker and A. Sethi, “Chagas disease: coming to a place near you,” Dermatologic Clinics, vol. 29, no. 1, pp. 53–62, 2011.
[2]
R. L. Tarleton, R. Reithinger, J. A. Urbina, U. Kitron, and R. E. Gürtler, “The challenges of Chagas disease—Grim outlook or glimmer of hope?” PLoS Medicine, vol. 4, no. 12, article e332, pp. 1852–1857, 2007.
[3]
J. R. Coura and J. C. P. Dias, “Epidemiology, control and surveillance of Chagas disease—100 years after its discovery,” Memorias do Instituto Oswaldo Cruz, vol. 104, supplement 1, pp. 31–40, 2009.
[4]
G. Punukollu, R. M. Gowda, I. A. Khan, V. S. Navarro, and B. C. Vasavada, “Clinical aspects of the Chagas' heart disease,” International Journal of Cardiology, vol. 115, no. 3, pp. 279–283, 2007.
[5]
K. M. Bonney and D. M. Engman, “Chagas heart disease pathogenesis: one mechanism or many?” Current Molecular Medicine, vol. 8, no. 6, pp. 510–518, 2008.
[6]
F. R. S. Gutierrez, P. M. M. Guedes, R. T. Gazzinelli, and J. S. Silva, “The role of parasite persistence in pathogenesis of Chagas heart disease,” Parasite Immunology, vol. 31, no. 11, pp. 673–685, 2009.
[7]
R. Sathler-Avelar, D. M. Vitelli-Avelar, A. Teixeira-Carvalho, and O. A. Martins-Filho, “Innate immunity and regulatory T-cells in human Chagas disease: what must be understood?” Memorias do Instituto Oswaldo Cruz, vol. 104, supplement 1, pp. 246–251, 2009.
[8]
W. Savino, D. M. S. Villa-Verde, D. A. Mendes-da-Cruz et al., “Cytokines and cell adhesion receptors in the regulation of immunity to Trypanosoma cruzi,” Cytokine and Growth Factor Reviews, vol. 18, no. 1-2, pp. 107–124, 2007.
[9]
J. De Meis, A. Morrot, D. A. Farias-de-Oliveira, D. M. S. Villa-Verde, and W. Savino, “Differential regional immune response in Chagas disease,” PLoS Neglected Tropical Diseases, vol. 3, no. 7, article e417, 2009.
[10]
J. de Meis, L. M. S. Ferreira, L. V. C. Guillermo, E. M. Silva, G. A. DosReis, and M. D. F. Lopes, “Apoptosis differentially regulates mesenteric and subcutaneous lymph node immune responses to Trypanosoma cruzi,” European Journal of Immunology, vol. 38, no. 1, pp. 139–146, 2008.
[11]
J. De Meis, D. A. Mendes-Da-Cruz, D. A. Farias-De-Oliveira et al., “Atrophy of mesenteric lymph nodes in experimental Chagas' disease: differential role of Fas/Fas-L and TNFRI/TNF pathways,” Microbes and Infection, vol. 8, no. 1, pp. 221–231, 2006.
[12]
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.
[13]
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.
[14]
M. C. Leite 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.
[15]
W. Savino, M. Do Carmo Leite-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.
[16]
M. D. C. Leite 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.
[17]
W. Savino, “The thymus is a common target organ in infectious diseases,” PLoS Pathogens, vol. 2, no. 6, aticle e62, pp. 0472–0483, 2006.
[18]
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.
[19]
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,” American Journal of Pathology, vol. 170, no. 2, pp. 546–556, 2007.
[20]
B. P. Olivieri, A. P. de Souza, V. Cotta-de-Almeida, S. L. de Castro, and T. Araújo-Jorge, “Trypanosoma cruzi: alteration in the lymphoid compartments following interruption of infection by early acute benznidazole therapy in mice,” Experimental Parasitology, vol. 114, no. 3, pp. 228–234, 2006.
[21]
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.
[22]
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.
[23]
E. Roggero, I. Piazzon, I. Nepomnaschy et al., “Thymocyte depletion during acute Trypanosoma cruzi infection in C57BL/6 mice is partly reverted by lipopolysaccharide pretreatment,” FEMS Immunology and Medical Microbiology, vol. 41, no. 2, pp. 123–131, 2004.
[24]
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.
[25]
M. S. Leguizamón, E. Mocetti, H. G. Rivello, P. Argibay, and O. Campetella, “Trans-sialidase from Trypanosoma cruzi induces apoptosis in cells from the immune system in vivo,” Journal of Infectious Diseases, vol. 180, no. 4, pp. 1398–1402, 1999.
[26]
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 e1268, 2011.
[27]
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.
[28]
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.
[29]
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.
[30]
W. Savino, D. A. Mendes-Da-Cruz, S. Smaniotto, E. Silva-Monteiro, and D. M. Serra 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.
[31]
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.
[32]
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.
[33]
M. Naspetti, M. Aurrand-Lions, J. DeKoning et al., “Thymocytes and RelB-dependent medullary epithelial cells provide growth-promoting and organization signals, respectively, to thymic medullary stromal cells,” European Journal of Immunology, vol. 27, no. 6, pp. 1392–1397, 1997.
[34]
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.
[35]
D. A. Mendes-da-Cruz, J. S. Silva, V. Cotta-de-Almeida, and W. Savino, “Altered thymocyte migration during experimental acute Trypanosoma cruzi infection: combined role of fibronectin and the chemokines CXCL12 and CCL4,” European Journal of Immunology, vol. 36, no. 6, pp. 1486–1493, 2006.
[36]
A. Cossarizza, C. Ortolani, D. Monti, and C. Franceschi, “Cytometric analysis of immunosenescence,” Cytometry, vol. 27, no. 4, pp. 297–313, 1997.
[37]
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.
[38]
P. M. Minoprio, A. Coutinho, and M. Joskowicz, “Polyclonal lymphocyte responses to murine Trypanosoma cruzi infection. II. Cytotoxic T lymphocytes,” Scandinavian Journal of Immunology, vol. 24, no. 6, pp. 669–679, 1986.
[39]
P. M. Minoprio, H. Eisen, and L. Forni, “Polyclonal lymphocyte responses to murine Trypanosoma cruzi infection. I. Quantitation of both T- and B-cell responses,” Scandinavian Journal of Immunology, vol. 24, no. 6, pp. 661–668, 1986.
[40]
A. R. Todeschini, M. P. Nunes, R. S. Pires et al., “Costimulation of host T lymphocytes by a trypanosomal trans-sialidase: involvement of CD43 signaling,” Journal of Immunology, vol. 168, no. 10, pp. 5192–5198, 2002.
[41]
W. Gao, H. H. Wortis, and M. A. Pereira, “The Trypanosoma cruzi trans-sialidase is a T cell-independent B cell mitogen and an inducer of non-specific Ig secretion,” International Immunology, vol. 14, no. 3, pp. 299–308, 2002.
[42]
B. Reina-San-Martín, W. Degrave, C. Rougeot et al., “A B-cell mitogen from a pathogenic trypanosome is a eukaryotic proline racemase,” Nature Medicine, vol. 6, no. 8, pp. 890–897, 2000.
[43]
M. A. Bryan and K. A. Norris, “Genetic immunization converts the Trypanosoma cruzi B-cell mitogen proline racemase to an effective immunogen,” Infection and Immunity, vol. 78, no. 2, pp. 810–822, 2010.
[44]
A. Buschiazzo, M. Goytia, F. Schaeffer et al., “Crystal structure, catalytic mechanism, and mitogenic properties of Trypanosoma cruzi proline racemase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 6, pp. 1705–1710, 2006.
[45]
P. Minoprio, O. Burlen, P. Pereira et al., “Most B cells in acute Trypanosoma cruzi infection lack parasite specificity,” Scandinavian Journal of Immunology, vol. 28, no. 5, pp. 553–561, 1988.
[46]
E. V. Acosta Rodriguez, E. I. Zuniga, C. L. Montes et al., “Trypanosoma cruzi infection beats the B-cell compartment favouring parasite establishment: can we strike first?” Scandinavian Journal of Immunology, vol. 66, no. 2-3, pp. 137–142, 2007.
[47]
L. B. De Arruda Hinds, M. S. Alexandre-Moreira, D. Decoté-Ricardo, M. P. Nunes, and L. M. T. Pe？anha, “Increased immunoglobulin secretion by B lymphocytes from Trypanosoma cruzi infected mice after B lymphocytes-natural killer cell interaction,” Parasite Immunology, vol. 23, no. 11, pp. 581–586, 2001.
[48]
N. Gironès, C. I. Rodríguez, E. Carrasco-Marín, R. F. Hernáez, J. López de Rego, and M. Fresno, “Dominant T- and B-cell epitopes in an autoantigen linked to Chagas' disease,” Journal of Clinical Investigation, vol. 107, no. 8, pp. 985–993, 2001.
[49]
C. Freire-De-Lima, L. M. T. Pe？anha, and G. A. Dos Reis, “Chronic experimental Chagas' disease: functional syngeneic T-B-cell cooperation in vitro in the absence of an exogenous stimulus,” Infection and Immunity, vol. 64, no. 7, pp. 2861–2866, 1996.
[50]
N. Yoshida, J. E. Araya, J. Franco Da Silveira, and S. Giorgio, “Trypanosoma cruzi: antibody production and T cell response induced by stage-specific surface glycoproteins purified from metacyclic trypomastigotes,” Experimental Parasitology, vol. 77, no. 4, pp. 405–413, 1993.
[51]
P. Minoprio, A. Coutinho, S. Spinella, and M. Hontebeyrie-Joskowicz, “Xid immunodeficiency imparts increased parasite clearance and resistance to pathology in experimental Chagas' disease,” International Immunology, vol. 3, no. 5, pp. 427–433, 1991.
[52]
A. M. Rodriguez, F. Santoro, and D. Afchain, “Trypanosoma cruzi infection in B-cell-deficient rats,” Infection and Immunity, vol. 31, no. 2, pp. 524–529, 1981.
[53]
J. W. Tung and L. A. Herzenberg, “Unraveling B-1 progenitors,” Current Opinion in Immunology, vol. 19, no. 2, pp. 150–155, 2007.
[54]
N. Baumgarth, M. Egerton, and A. Kelso, “Activated T cells from draining lymph nodes and an effector site differ in their responses to TCR stimulation,” Journal of Immunology, vol. 159, no. 3, pp. 1182–1191, 1997.
[55]
W. O. Dutra, D. G. Colley, J. C. Pinto-Dias et al., “Self and nonself stimulatory molecules induce preferential expansion of CD5+B cells or activated T cells of chagasic patients, respectively,” Scandinavian Journal of Immunology, vol. 51, no. 1, pp. 91–97, 2000.
[56]
M. C. El Cheikh, M. Hontebeyrie-Joskowicz, A. Coutinho, and P. Minoprio, “CD5 B cells: potential role in the (auto)immune responses to Trypanosoma cruzi infection,” Annals of the New York Academy of Sciences, vol. 651, pp. 557–563, 1992.
[57]
F. S. Mariano, F. R. S. Gutierrez, W. R. Pavanelli et al., “The involvement of CD4+CD25+ T cells in the acute phase of Trypanosoma cruzi infection,” Microbes and Infection, vol. 10, no. 7, pp. 825–833, 2008.
[58]
P. Pandiyan, L. Zheng, S. Ishihara, J. Reed, and M. J. Lenardo, “CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells,” Nature Immunology, vol. 8, no. 12, pp. 1353–1362, 2007.
[59]
H. H. Uhlig, C. Mottet, and F. Powrie, “Homing of intestinal immune cells,” Novartis Foundation Symposium, vol. 263, pp. 179–188, 2004.
[60]
E. M. Lemos, D. D. Reis, S. J. Adad, G. C. Silva, E. Crema, and R. Correa-Oliveira, “Decreased CD4+ circulating T lymphocytes in patients with gastrointestinal Chagas disease,” Clinical Immunology and Immunopathology, vol. 88, no. 2, pp. 150–155, 1998.
[61]
E. Crema, I. D. O. Monteiro, M. G. Z. Gomes, A. A. Silva, and V. Rodrigues Júnior, “Evaluation of cytokines (MIG, IFN-γ, TNF-α, IL-4, IL-5, and IL-10) during the different evolutive phases of chagasic esophagopathy,” Clinical Immunology, vol. 119, no. 2, pp. 213–218, 2006.
