Are increased frequency of macrophage-like and natural killer (NK) cells, together with high levels of NKT and CD4+CD25high T cells balancing activated CD8+ T cells, the key to control Chagas’ disease morbidity?

Abstract

The immunological response during early human Trypanosoma cruzi infection is not completely understood, despite its role in driving the development of distinct clinical manifestations of chronic infection. Herein we report the results of a descriptive flow cytometric immunophenotyping investigation of major and minor peripheral blood leucocyte subpopulations in T. cruzi-infected children, characterizing the early stages of the indeterminate clinical form of Chagas' disease. Our results indicated significant alterations by comparison with uninfected children, including increased values of pre-natural killer (NK)-cells (CD3- CD16+ CD56-), and higher values of proinflammatory monocytes (CD14+ CD16+ HLA-DR++). The higher values of activated B lymphocytes (CD19+ CD23+) contrasted with impaired T cell activation, indicated by lower values of CD4+ CD38+ and CD4+ HLA-DR+ lymphocytes, a lower frequency of CD8+ CD38+ and CD8+ HLA-DR+ cells; a decreased frequency of CD4+ CD25HIGH regulatory T cells was also observed. These findings reinforce the hypothesis that simultaneous activation of innate and adaptive immunity mechanisms in addition to suppression of adaptive cellular immune response occur during early events of Chagas' disease. Comparative cross-sectional analysis of these immunophenotypes with those exhibited by patients with late chronic indeterminate and cardiac forms of disease suggested that a shift toward high values of macrophage-like cells extended to basal levels of proinflammatory monocytes as well as high values of mature NK cells, NKT and regulatory T cells, may account for limited tissue damage during chronic infection favouring the establishment/maintenance of a lifelong indeterminate clinical form of the disease. On the other hand, development of an adaptive cell-mediated inflammatory immunoprofile characterized by high levels of activated CD8+ cells and basal levels of mature NK cells, NKT and CD4+ CD25HIGH cells might lead to late chronic pathologies associated with chagasic heart disease.

Current concepts in immunoregulation and pathology of human Chagas disease

“…The higher expression of IL-10 by cells from indeterminate as compared with cardiac patients was also observed by other groups [43]. Moreover, a high frequency of CD4+CD25 cells has been observed in indeterminate patients [28]. An intriguing finding was that although CD8+ T cells from indeterminate patients display a high frequency of surface CTLA-4 expression, the same cells from cardiac patients have lower surface expression of CTLA-4, while intracellular expression was high [48 •• ].…”

“…Although classic studies have suggested a suppressive response in the early phases of human T. cruzi infection [24,25], it is clear that the immune response mounted is efficient for controlling patent parasitemia. It has been suggested that B-cell activation leading to lytic antibody production is important in parasite elimination during the acute phase [26][27][28]. Although studies of endomyocardial biopsies from acute patients have shown the presence of CD4+ and CD8+ T cells in the inflammatory myocarditis [29], the function of these cells during the acute phase has not been determined.…”

Cutting Edge: Small Molecule CD40 Ligand Mimetics Promote Control of Parasitemia and Enhance T Cells Producing IFN-γ during ExperimentalTrypanosoma cruziInfection

“…Significant differences as shown on days 21 and 28 postinfection for C1 (100 g) vs NaCl (p Ͻ 0.02) and on day 21 postinfection for C1 (10 g) vs NaCl (p Ͻ 0.04). as CD4 ϩ and NK cells in immune protection against infection (12). Based on the protective capacity of miniCD40Ls peptides, one may speculate on the role of these potent immunocompetent cells through CD40-CD40L signaling.…”

Pathogenesis and Pathology of Chagas' Chronic Myocarditis

“…The role of NK cells has been particularly studied in early and late indeterminate forms of the disease and in CCC patients. In early indeterminate patients, (Girones, et al, 2005, Marin-Neto, et al, 2007 -Avelar, et al, 2006). This profile may be useful to limit parasitemia and confine infection to tissues.…”