title: 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.
abstract: Extrathymic CD4+CD8+ double-positive (DP) T cells are increased in some pathophysiological conditions, including infectious diseases. In the murine model of Chagas disease, it has been shown that the protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironment and the lymphoid compartment. In the acute phase, this results in a severe atrophy of the organ and early release of DP cells into the periphery. To date, the effect of the changes promoted by the parasite infection on thymic central tolerance has remained elusive. Herein we show that the intrathymic key elements that are necessary to promote the negative selection of thymocytes undergoing maturation during the thymopoiesis remains functional during the acute chagasic thymic atrophy. Intrathymic expression of the autoimmune regulator factor (Aire) and tissue-restricted antigen (TRA) genes is normal. In addition, the expression of the proapoptotic Bim protein in thymocytes was not changed, revealing that the parasite infection-induced thymus atrophy has no effect on these marker genes necessary to promote clonal deletion of T cells. In a chicken egg ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic system, the administration of OVA peptide into infected mice with thymic atrophy promoted OVA-specific thymocyte apoptosis, further indicating normal negative selection process during the infection. Yet, although the intrathymic checkpoints necessary for thymic negative selection are present in the acute phase of Chagas disease, we found that the DP cells released into the periphery acquire an activated phenotype similar to what is described for activated effector or memory single-positive T cells. Most interestingly, we also demonstrate that increased percentages of peripheral blood subset of DP cells exhibiting an activated HLA-DR+ phenotype are associated with severe cardiac forms of human chronic Chagas disease. These cells may contribute to the immunopathological events seen in the Chagas disease.
authors.affiliation: Department of Immunology, Microbiology Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. morrot@micro.ufrj.br
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morrot
authors.forename: Eugênia
authors.initials: E
authors.lastname: Terra-Granado
authors.forename: Ana Rosa
authors.initials: AR
authors.lastname: Pérez
authors.forename: Suse Dayse
authors.initials: SD
authors.lastname: Silva-Barbosa
authors.forename: Novica M
authors.initials: NM
authors.lastname: Milićević
authors.forename: Désio Aurélio
authors.initials: DA
authors.lastname: Farias-de-Oliveira
authors.forename: Luiz Ricardo
authors.initials: LR
authors.lastname: Berbert
authors.forename: Juliana
authors.initials: J
authors.lastname: De Meis
authors.forename: Christina Maeda
authors.initials: CM
authors.lastname: Takiya
authors.forename: Juan
authors.initials: J
authors.lastname: Beloscar
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.forename: Vivian
authors.initials: V
authors.lastname: Kont
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.forename: Oscar
authors.initials: O
authors.lastname: Bottasso
authors.forename: Wilson
authors.initials: W
authors.lastname: Savino
mesh_terms: D000328:Adult; D000818:Animals; D001284:Atrophy / Q000473:pathology*; D015704:CD4 Antigens / Q000032:analysis*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D016827:CD8 Antigens / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D014355:Chagas Disease / Q000150:complications* / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000737:chemistry* / Q000276:immunology*; D013950:Thymus Gland / Q000473:pathology*; D014349:Trypanosoma cruzi / Q000276:immunology / Q000472:pathogenicity
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens