Low Frequency of Circulating CD8+ T Stem Cell Memory Cells in Chronic Chagasic Patients with Severe Forms of the Disease

Abstract

BackgroundCD8+ T cells have been shown to play a crucial role in Trypanosoma cruzi infection. Memory CD8+ T cells can be categorised based on their distinct differentiation stages and functional activities as follows: stem cell memory (TSCM), central memory (TCM), transitional memory (TTM), effector memory (TEM) and terminal effector (TTE) cells. Currently, the immune mechanisms that control T. cruzi in the chronic phase of the infection are unknown.Methodology/Principal FindingsTo characterise the CD8+ T cell subsets that could be participating in the control of T. cruzi infection, in this study, we compared total and T. cruzi-specific circulating CD8+ T cells with distinctive phenotypic and functional features in chronic chagasic patients (CCPs) with different degrees of cardiac dysfunction. We observed a decreased frequency of total TSCM along with an increased frequency of TTE in CCPs with severe disease. Antigen-specific TSCM cells were not detectable in CCPs with severe forms of the disease. A functional profile of CD8+ T cell subsets among CCPs revealed a high frequency of monofunctional CD8+ T cells in the most severe patients with IFN-γ+- or TNF-α+-producing cells.Conclusions/SignificanceThese findings suggest that CD8+ TSCM cells may be associated with the immune response to T. cruzi and outcome of Chagas disease, given that these cells may be involved in repopulating the T cell pool that controls infection.

Memory Stem T Cells in Autoimmune Disease: High Frequency of Circulating CD8+ Memory Stem Cells in Acquired Aplastic Anemia

“…TSCM have been examined in infectious diseases (25, 31, 32), in the development of immunotherapies and vaccines for cancer (33, 34), in allogeneic hematopoietic stem cell transplantation (35, 36), and in adult T-cell leukemia (37). TSCM represent the earliest and longest lasting developmental stage of memory T cells and exhibit a gene expression profile between TN and TCM cells (12, 18).…”

T cells responding to Trypanosoma cruzi detected by membrane TNF‐α and CD154 in chagasic patients

“…A recent investigation used three intracellular cytokines (IFN-g, TNF-a, or IL-2) as markers of CD8þ T cell functionality [23]. Upon parasite stimuli, asymptomatic chagasic patients displayed a higher percentage of bifunctional (IFN-gþ/TNF-aþ) T cells, while symptomatic chagasic patients displayed a higher percentage of monofunctional T cells (IFN-gþ or TNF-aþ) [23]. Regardless of the phenotype, TNF-a seemed to be the cytokine most consistently secreted among T cell subpopulations in chronic chagasic patients [10,23].…”

“…Upon parasite stimuli, asymptomatic chagasic patients displayed a higher percentage of bifunctional (IFN-gþ/TNF-aþ) T cells, while symptomatic chagasic patients displayed a higher percentage of monofunctional T cells (IFN-gþ or TNF-aþ) [23]. Regardless of the phenotype, TNF-a seemed to be the cytokine most consistently secreted among T cell subpopulations in chronic chagasic patients [10,23]. Thus, similar to T cell exhaustion in viral models, IL-2 secretion is hampered while TNF-a is maintained, even in advanced phases of Chagas disease (cardiac manifestations) in which antigenic-specific T cells displayed an effector rather than memory T cell phenotype [10,23].…”

“…No. 579050; San Diego, CA, USA) under the following conditions: (1) cells in RPMI 1640 media alone; (2) 10 mg/ml of T. cruzi trypomastigote-lysate [23]; and (3) 3.7 mg/ml of Staphylococcal enterotoxin B (SEB). After culture, cells were washed with 0.01 M PBS pH 7.4 (or PBS 1Â) followed by surface staining with anti-CD3 APC (clone SK7), anti-CD4 PerCP (SK3), CD8-APCH7 (SK1), anti-CD154 PE (TRAP1).…”

“…In chronic Chagas disease, T. cruzi-specific T cell function is altered [21][22][23]. T cell IFN-g secretion is diminished as cardiac disease progresses, rendering it necessary to identify other markers of antigen T cell specificity [7,24].…”