T-cell receptor variable region usage in Chagas disease: A systematic review of experimental and human studies

Abstract

T cells recognize their ligand, the peptide major histocompatibility complex (MHC), via the T-cell receptor (TCR), which is composed of covalently linked α and β or γ and δ chains. This recognition is critical for T-cell ontogeny and controls the selection, activation, and function of T lymphocytes. Specific TCR αβ variable regions have been associated with immunopathogenesis of Chagas disease. Here, we present a systematic review that compiles experimental in vivo and human data regarding the preferential expression of variable alpha (Vα) and variable beta (Vβ) chain regions in Trypanosoma cruzi infection. The original studies indexed in PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. The analysis showed that expression of TCR Vα subfamilies were evaluated in one human study, and, unlike TCR Vβ, TCR Vα presented a more restricted usage. Despite the great variability in the usage of TCR Vβ regions in human Chagas disease, a down-regulation of TCR Vβ5 expression by T cells from patients in the acute phase of the disease was shown. Opposingly, this TCR region was found overly expressed in CD4+ T cells from chronic Chagas patients. It was also demonstrated that murine Vβ9+ T cells derived from nonlymphoid organs of T . cruzi -infected animals had a modulatory profile, while splenic Vβ9+ T cells produced inflammatory cytokines, indicating that although they display the same TCR Vβ region usage, these cells are functionally distinct. Despite the limitations of few papers and year of publication of the studies, compiling the data derived from them reveals that further investigation of TCR usage will point to their potential role in protective or pathogenic responses, as biomarkers of disease progression, and in the search for dominant peptides potentially useful for the development of vaccines or therapies.

Immunoglobin and T cell receptor repertoire changes induced by a prototype vaccine against Chagas disease in naïve rhesus macaques

“…The IgG repertoire showed a rapid turnover with new IgGs following each vaccine dose, while the TCR repertoire presented persisting clones that were expanded after each vaccine dose, suggesting that three vaccine doses may be needed for optimum e cacy. This work warrants the further characterization of the IgG and T cell receptor repertoires of Chagas disease patients 41 , particularly with different stages of disease progression/parasite control, to identify immune repertoire pro les associated with better disease outcomes and correlates for protection. Also, the evaluation of the protective e cacy of this vaccine candidate against T. cruzi infection will be key for vaccine development and the availability of naturally-infected macaques provide an ideal model for testing a therapeutic vaccine 42 .…”

Brain-Thymus connections in Chagas Disease

“…Several studies indicate that T. cruzi -driven thymic atrophy is caused by an immunoneuroendocrine imbalance [5, 14], added to the fact that thymic abnormalities can persist during the chronic phase of infection [18‒20]. These findings increase the suspicion that thymic affectation might provoke defects in the mechanisms responsible for central tolerance and that could be related to the establishment of CCC, although this issue remains uncertain [19, 21]. Anyhow, the study of thymus-brain interrelationships that take place in the context of Chagas disease could provide interesting clues to disclose important issues related to pathophysiological and disturbing effects upon the thymus, which may be of relevance in terms of both thymic selection and T-cell mediated immune response.…”

“…By now, we do not know whether changes in GC levels during T. cruzi infection alter per se the repertoire. However, diverse changes in the peripheral T-cell repertoire were reported after T. cruzi infection [18, 20, 21, 58, 59]. The most striking is that potentially auto-reactive DP T-cells can be tracked in the heart and lymphoid organs of infected animals and also in the blood of individuals with chronic Chagas disease [16], suggesting that they have bypassed the events of negative selection.…”