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Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, presents a substantial global health burden, affecting millions of individuals worldwide and posing a continual risk of infection. Despite the high mortality and morbidity rates, effective vaccines to prevent infection by the parasite remain elusive, and the drugs currently available are suboptimal. Understanding the intricate dynamics of parasite-host interactions and the resulting immune responses, which contribute to both protection and pathology, is crucial for the development of effective vaccines and therapies against Chagas disease. In this Series paper, we discuss the challenges associated with discovering and translating prophylactic and therapeutic strategies from the laboratory bench to clinical application. We highlight ongoing efforts in vaccine and new drug development, with a focus on more advanced candidates for vaccines and drugs. We also discuss potential solutions, emphasising the importance of collaborative research efforts, sustained funding, and a comprehensive understanding of host-parasite interactions and immunopathology to advance the development of new vaccines and therapies against Chagas disease., Competing Interests: Declaration of interests We declare no competing interests. MJP and J-RI are affiliated with DNDi, which oversees the development of Chagas disease treatments, some of which are highlighted in this Series paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The complexity of host-pathogen interactions often leads to distinct clinical outcomes upon infection with different pathogen strains. In this Review, we explore the interactions between the highly diverse Trypanosoma cruzi population and the human host. At least 30% of the 7 million individuals with Chagas disease will develop a severe cardiopathy that is among the deadliest heart diseases known. The diversity of the T cruzi population also creates major hurdles for therapy and vaccine development. We also discuss the ecoepidemiological and geographical distribution of T cruzi strains, their susceptibility to treatment, their antigenic diversity, and their effect on the immune response and on disease outcome. Furthermore, we highlight the importance of understanding the T cruzi host-pathogen relationship for guiding new approaches towards development of therapies and vaccines for Chagas disease, and how the information gained by studying this relationship can inspire solutions for other host-pathogen interactions., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Increasing attention has been directed to cytotoxic CD4 + T cells (CD4CTLs) in different pathologies, both in humans and mice. The impact of CD4CTLs in immunity and the mechanisms controlling their generation, however, remain poorly understood. Here, we show that CD4CTLs abundantly differentiate during mouse infection with the intracellular parasite Trypanosoma cruzi . CD4CTLs display parallel kinetics to Th1 cells in the spleen, mediate specific cytotoxicity against cells presenting pathogen-derived antigens and express immunoregulatory and/or exhaustion markers. We demonstrate that CD4CTL absolute numbers and activity are severely reduced in both Myd88 -/- and Il18ra -/- mice. Of note, the infection of mixed-bone marrow chimeras revealed that wild-type (WT) but not Myd88 -/- cells transcribe the CD4CTL gene signature and that Il18ra -/- and Myd88 -/- CD4 + T cells phenocopy each other. Moreover, adoptive transfer of WT CD4 + GzB + T cells to infected Il18ra -/- mice extended their survival. Importantly, cells expressing the CD4CTL phenotype predominate among CD4 + T cells infiltrating the infected mouse cardiac tissue and are increased in the blood of Chagas patients, in which the frequency of CD4CTLs correlates with the severity of cardiomyopathy. Our findings describe CD4CTLs as a major player in immunity to a relevant human pathogen and disclose T-cell intrinsic IL-18R/MyD88 signaling as a key pathway controlling the magnitude of the CD4CTL response., Competing Interests: CB, FC, AG, LB, JL, GM, AG, EN, WD, AO, AN, MB No competing interests declared, (© 2022, Barbosa, Canto, Gomes et al.)

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that has a heterogeneous population composed of a pool of strains with distinct characteristics, including variable levels of virulence. In previous work, transcriptome analyses of parasite genes after infection of human foreskin fibroblasts (HFF) with virulent (CL Brener) and non-virulent (CL-14) clones derived from the CL strain, revealed a reduced expression of genes encoding parasite surface proteins in CL-14 compared to CL Brener during the final steps of the intracellular differentiation from amastigotes to trypomastigotes. Here we analyzed changes in the expression of host genes during in vitro infection of HFF cells with the CL Brener and CL-14 strains by analyzing total RNA extracted from cells at 60 and 96 hours post-infection (hpi) with each strain, as well as from uninfected cells. Similar transcriptome profiles were observed at 60 hpi with both strains compared to uninfected samples. However, at 96 hpi, significant differences in the number and expression levels of several genes, particularly those involved with immune response and cytoskeleton organization, were observed. Further analyses confirmed the difference in the chemokine/cytokine signaling involved with the recruitment and activation of immune cells such as neutrophils upon T. cruzi infection. These findings suggest that infection with the virulent CL Brener strain induces a more robust inflammatory response when compared with the non-virulent CL-14 strain. Importantly, the RNA-Seq data also exposed an unexplored role of fibroblasts as sentinel cells that may act by recruiting neutrophils to the initial site of infection. This role for fibroblasts in the regulation of the inflammatory response during infection by T. cruzi was corroborated by measurements of levels of different chemokines/cytokines during in vitro infection and in plasma from Chagas disease patients as well as by neutrophil activation and migration assays., Competing Interests: The authors have declared that no competing interests exist.

Aims: The aim of the study was to evaluate the immune response triggered by the first contact of human monocytes with two T cruzi strains from distinct discrete typing units (DTUs) IV and V, and whether co-infection with these strains leads to changes in monocyte immune profiles, which could in turn influence the subsequent infection outcome., Methods and Results: We evaluated the influence of in vitro single- and co-infection with AM64 and 3253 strains on immunological characteristics of human monocytes. Single infection of monocytes with AM64 or 3253 induced opposing anti-inflammatory and inflammatory responses, respectively. Co-infection was observed in over 50% of monocytes after 15 hours of culture, but this percentage dropped ten-fold after 72 hours. Co-infection led to high monocyte activation and an increased percentage of both IL-10 and TNF. The decreased percentage of co-infected cells observed after 72 hours was associated with a decreased frequency of TNF-expressing cells., Conclusion: Our results show that the exacerbated response observed in co-infection with immune-polarizing strains is associated with a decreased frequency of co-infected cells, suggesting that the activated response favours parasite control. These findings may have implications for designing new Chagas disease preventive strategies., (© 2019 John Wiley & Sons Ltd.)

Introduction: Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the fourth most important tropical disease, which affects approximately 7 million people worldwide. The mechanisms involved in the development of this disease are not completely well understood. An important protective role of regulatory T cells (Treg) in Chagas disease has been observed; however, the specific mechanisms remain unclear. We evaluated apoptosis as a possible mechanism mediated by Treg cells (CD4 + CD25 High FOXP3 + ) to orchestrate the immune response in chronic Chagas disease., Methods and Results: Patients with Chagas disease were grouped as the indeterminate (IND; asymptomatic patients with Chagas disease; n = 10) and dilated cardiomyopathy (CARD; n = 10). Healthy T. cruzi-negative individuals (NI; n = 10) were included as a control group. In order to evaluate the apoptotic cell profile, the expression of PD1, PD1L, CD39, CD95, CD95L molecules were investigated. We also evaluated the proportion of CD14 + cells expressing caspase 3. The IND group presented a substantially higher expression of CD39 by Treg cells as compared to the CARD group. On the other hand, the CARD group showed higher expression of PD-1 by Treg cells than both NI and IND groups. Significant positive correlations were observed between Treg CD95L + cells and CD14 cells expressing caspase 3 as well as between Treg CD39 cells and CD14 + Caspase3 + cells in the IND group., Conclusion: Our data indicate that the expressions of different molecules that induce apoptosis are associated with suppressive mechanisms mediated by Treg cells and suggest a possible role for PD1 and PDL1 molecules in the morbidity of chronic Chagas disease., (Copyright © 2019 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: Chagas disease, resulting from the protozoan Trypanosoma cruzi, is an important cause of heart failure, stroke, arrhythmia, and sudden death. Traditionally regarded as a tropical disease found only in Central America and South America, Chagas disease now affects at least 300 000 residents of the United States and is growing in prevalence in other traditionally nonendemic areas. Healthcare providers and health systems outside of Latin America need to be equipped to recognize, diagnose, and treat Chagas disease and to prevent further disease transmission., Methods and Results: The American Heart Association and the Inter-American Society of Cardiology commissioned this statement to increase global awareness among providers who may encounter patients with Chagas disease outside of traditionally endemic environments. In this document, we summarize the most updated information on diagnosis, screening, and treatment of T cruzi infection, focusing primarily on its cardiovascular aspects. This document also provides quick reference tables, highlighting salient considerations for a patient with suspected or confirmed Chagas disease., Conclusions: This statement provides a broad summary of current knowledge and practice in the diagnosis and management of Chagas cardiomyopathy. It is our intent that this document will serve to increase the recognition of Chagas cardiomyopathy in low-prevalence areas and to improve care for patients with Chagas heart disease around the world.

In the chronic phase of Chagas disease, 60% of the patients develop the asymptomatic form known as indeterminate (IND). The remaining 30% of the patients develop a life-threatening form in which digestive and/or cardiac (CARD) alterations take place. The mechanisms underlying the development of severe forms of Chagas disease remain poorly understood. It is well known that interactions between immune cells such as monocytes and lymphocytes drive immune responses. Further, the co-stimulatory molecules CD80 and CD86 expressed by monocytes and subsets induce lymphocyte activation, thereby triggering cellular immune response. Here, we revealed, for the first time, the functional-phenotypic profile of monocytes subsets in Chagas disease. Using flow cytometry, we evaluated the effect of in vitro stimulation with Trypanosoma cruzi antigens on the expression of the co-stimulatory molecules CD80 and CD86 in different monocyte subsets of patients with IND and CARD clinical forms of Chagas disease. We also assessed the expression of toll-like receptor (TLR)-2, TLR-4, TLR-9, HLA-DR, IL-10, and IL-12 in the monocyte subsets and of CTLA-4 and CD28, ligands of CD80 and CD86, in T lymphocytes. CD86 expression in all monocyte subsets was higher in IND patients when compared with non-infected (NI) individuals. After stimulation with T. cruzi , these patients also showed a higher frequency of CD4 + CTLA-4 + T lymphocytes than NI individuals. We found an association between CD80 and CD28, and between CD86 and CTLA-4 expression, with a high frequency of regulatory T (Treg) cells in IND patients. We proposed that CD86 may be involved in immunoregulation by its association with CTLA-4 in asymptomatic patients. CD86 and CTLA-4 interaction may influence Treg activation, and this could represent a new strategy to control inflammation and tissue damage.

Neutrophils are critical players in the first line of defense against pathogens and in the activation of subsequent cellular responses. We aimed to determine the effects of the interaction of Trypanosoma cruzi with human neutrophils, using isolates of the two major discrete type units (DTUs) associated with Chagas' disease in Latin America (clone Col1.7G2 and Y strain, DTU I and II, respectively). Thus, we used CFSE-stained trypomastigotes to measure neutrophil-T. cruzi interaction, neutrophil activation, cytokine expression and death, after infection with Col1.7G2 and Y strain. Our results show that the frequency of CFSE+ neutrophils, indicative of interaction, and CFSE intensity on a cell-per-cell basis were similar when comparing Col1.7G2 and Y strains. Interaction with T. cruzi increased neutrophil activation, as measured by CD282, CD284, TNF and IL-12 expression, although at different levels between the two strains. No change in IL-10 expression was observed after interaction of neutrophils with either strain. We observed that exposure to Y and Col1.7G2 caused marked neutrophil death. This was specific to neutrophils, since interaction of either strain with monocytes did not cause death. Our further analysis showed that neutrophil death was a result of apoptosis, which was associated with an upregulation of TNF-receptor, TNF and FasLigand, but not of Fas. Induction of TNF-associated neutrophil apoptosis by the different T. cruzi isolates may act as an effective common mechanism to decrease the host's immune response and favor parasite survival.

Background: Trypanosoma cruzi strains are currently classified into six discrete typing units (DTUs) named TcI to VI. It is known that these DTUs have different geographical distribution, as well as biological features. TcI and TcII are major DTUs found in patients from northern and southern Latin America, respectively. Our hypothesis is that upon infection of human peripheral blood cells, Y strain (Tc II) and Col cl1.7 (Tc I), cause distinct immunological changes, which might influence the clinical course of Chagas disease., Methodology/principal Findings: We evaluated the infectivity of CFSE-stained trypomastigotes of Col cl1.7 and Y strain in human monocytes for 15 and 72 hours, and determined the immunological profile of lymphocytes and monocytes exposed to the different isolates using multiparameter flow cytometry. Our results showed a similar percentage and intensity of monocyte infection by Y and Col cl1.7. We also observed an increased expression of CD80 and CD86 by monocytes infected with Col cl1.7, but not Y strain. IL-10 was significantly higher in monocytes infected with Col cl1.7, as compared to Y strain. Moreover, infection with Col cl1.7, but not Y strain, led to an increased expression of IL-17 by CD8+ T cells. On the other hand, we observed a positive correlation between the expression of TNF-alpha and granzyme A only after infection with Y strain., Conclusion/significance: Our study shows that while Col cl1.7 induces higher monocyte activation and, at the same time, production of IL-10, infection with Y strain leads to a lower monocyte activation but higher inflammatory profile. These results show that TcI and TcII have a distinct immunological impact on human cells during early infection, which might influence disease progression.

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi, and although over 100 years have passed since the discovery of Chagas disease, it still presents an increasing problem for global public health. A plethora of information concerning the chronic phase of human Chagas disease, particularly the severe cardiac form, is available in the literature. However, information concerning events during the acute phase of the disease is scarce. In this review, we will discuss (1) the current status of acute Chagas disease cases globally, (2) the immunological findings related to the acute phase and their possible influence in disease outcome, and (3) reactivation of Chagas disease in immunocompromised individuals, a key point for transplantation and HIV infection management.

Chagas disease caused by Trypanosoma cruzi remains an important neglected tropical disease and a cause of significant morbidity and mortality. No longer confined to endemic areas of Latin America, it is now found in non-endemic areas due to immigration. The parasite may persist in any tissue, but in recent years, there has been increased recognition of adipose tissue both as an early target of infection and a reservoir of chronic infection. The major complications of this disease are cardiomyopathy and megasyndromes involving the gastrointestinal tract. The pathogenesis of Chagas disease is complex and multifactorial involving many interactive pathways. The significance of innate immunity, including the contributions of cytokines, chemokines, reactive oxygen species, and oxidative stress, has been emphasized. The role of the components of the eicosanoid pathway such as thromboxane A(2) and the lipoxins has been demonstrated to have profound effects as both pro- and anti-inflammatory factors. Additionally, we discuss the vasoconstrictive actions of thromboxane A(2) and endothelin-1 in Chagas disease. Human immunity to T. cruzi infection and its role in pathogen control and disease progression have not been fully investigated. However, recently, it was demonstrated that a reduction in the anti-inflammatory cytokine IL-10 was associated with clinically significant chronic chagasic cardiomyopathy.

CD4(-) CD8(-) (double-negative [DN]) T cells have recently been shown to display important immunological functions in human diseases. They express γδ or αβ T-cell receptors that recognize lipid/glycolipid antigens presented via the nonclassical major histocompatibility complex molecules of the CD1 family. We recently demonstrated that while αβ DN T cells serve primarily to express inflammatory cytokines, γδ DN T cells express mainly interleukin-10 (IL-10) in patients with cutaneous leishmaniasis. We also demonstrated a correlation between DN T cells and the expression of gamma interferon in the acute phase of Trypanosoma cruzi experimental infection. In this work, we sought to investigate whether αβ or γδ DN T cells display distinct immunoregulatory potentials in patients with polar forms of human Chagas' disease. Our data showed that in vitro infection with T. cruzi leads to expansion of DN T cells in patients with the indeterminate and severe cardiac clinical forms of the disease. However, while αβ DN T cells primarily produce inflammatory cytokines in both forms of the disease, γδ DN T cells display a marked, significant increase in antigen-specific IL-10 expression in indeterminate patients relative to cardiac patients. Finally, higher frequencies of the IL-10-producing γδ DN T cells were correlated with improved clinical measures of cardiac function in the patients, suggesting a protective role for these cells in Chagas' disease. Taken together, these data show distinct functional characteristics for αβ and γδ DN T cells associated with distinct morbidity rates and clinical forms in human Chagas' disease.

Purpose of Review: Chagas disease is a complex ailment caused by infection with Trypanosoma cruzi. It afflicts millions in Latin America. Years of studies have focused on the development of pathology in Chagas disease and recent studies have helped us understand the cellular mechanisms behind differential clinical evolution of Chagas disease., Recent Findings: We discuss recent findings concerning the cellular immune response in human Chagas disease focusing on immunoregulation and the development of pathology. We seek to put several findings into the context of a disease that initially controls an extreme and patent infection, and later progresses to a chronic phase marked by the presence (cardiac and digestive forms), or not (indeterminate form), of associated pathology., Summary: Several theories exist to explain differential clinical evolution of Chagas disease. A coherent understanding of these theories will certainly aid in determining what combination of them approximates the true development of chagasic pathology. For achieving the goal of developing a successful therapy or intervention, it is critical that no theory be excluded at this point, but. Rather, rather that a thoughtful analysis and assimilation of the best components of each system into a central theory that best fits the reality of human Chagas disease is desirable.

The JG strain is the least virulent while the CL-Brener clone is one of the most virulent Trypanosoma cruzi populations in young rats. In this study, we determined that the parasitemia peak values in CL-Brener clone-infected adult rats were 50-fold lower than in young rats and that mortality was null as compared to 45% death in young rats. Low parasitemia, milder and sustained myocarditis and myositis characterized JG infections. CL-Brener clone caused a significantly higher production of pro-inflammatory cytokines and higher expansion of CD3(+)CD4(-)CD8(-), double-negative (DN) T cells, during the acute phase in both adult and young rats. DN T cell frequencies correlated with IFN-gamma levels. These findings may explain the higher inflammation and fast acute phase resolution in CL-Brener infection. In young rats, IL-10 levels were similar in both infections. The IL-10/IFN-gamma ratio was higher in JG acute infection in accordance with the milder inflammation and parasite persistence leading to a chronic phase. In conclusion, virulence and pathogenicity depend on T. cruzi ability to induce expansion of DN T cells and production of specific cytokines.

Human infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects approximately 17 million people in Latin America. A significant percentage of the infected population will develop clinical symptoms or present changes in laboratory and/or image evaluation. The existence of a large spectrum of clinical manifestations--with patients ranging from asymptomatic to severe cardiac involvement--emphasizes the need to use standardized and well-defined clinical criteria among different research groups. In this article, we carry out a systematic review of the immunology in human Chagas disease, discussing recent findings in the context of a clinical perspective.

Dilated cardiomyopathy, the most severe manifestation in chronic phase of Chagas disease, affects about 30% of patients and is characterized by myocardial dysfunction and interstitial fibrosis due to extracellular matrix (ECM) remodeling. ECM remodeling is regulated by proteolytic enzymes such as matrix metalloproteinases (MMPs) and cytokines produced by immune cells, including phagocytes. We evaluated by flow cytometry the expression of MMP-2, MMP-9, IL-1β, TNF-α, TGF-β and IL-10 by neutrophils and monocytes from patients with indeterminate (IND) and cardiac (CARD) clinical forms of Chagas disease and non-infected individuals (NI), before and after in vitro stimulation with Trypanosoma cruzi antigens. Our results showed an important contribution of neutrophils for MMPs production, while monocytes seemed to be involved in cytokine production. The results showed that neutrophils and monocytes from IND and CARD patients had higher intracellular levels of MMP-2 and MMP-9 than NI individuals. On the other hand, T. cruzi derived-antigens promote a differential expression of MMP-2 and MMP-9 in patients with Chagas disease and may regulate MMPs expression in neutrophils and monocytes, mainly when a cardiac alteration is not present. Our data also showed that in the presence of T. cruzi derived-antigens the production of cytokines by neutrophils and monocytes, but mainly by monocytes, may be intensified. Correlation analysis demonstrated that MMP-2 had a positive correlation with IL-10 and a negative correlation with IL-1β, whereas MMP-9 showed a negative correlation with IL-10. We also observed that IND patients presented a greater percentage of high producer cells of regulatory molecules when compared to CARD patients, indicating a different pattern in the immune response. Our data suggest that MMPs and cytokines produced by neutrophils and monocytes are important contributors for cardiac remodeling and may be an interesting target for new biomarker research. [ABSTRACT FROM AUTHOR]

This study was designed to determine whether the functional IL-10 gene polymorphism -1082G/A is associated with the development of cardiomyopathy in individuals infected with Trypanosoma cruzi and whether interleukin (IL)-10 expression can be correlated with patients' cardiac function. Our results demonstrated that the polymorphic allele, which correlates with lower expression of IL-10, was associated with the development of Chagas disease cardiomyopathy. Accordingly, correlative analysis showed that low IL-10 expression was associated with worse cardiac function, as determined by leftventricular ejection fraction values. Therefore, the IL-10 gene polymorphism and IL-10 expression are important in determining susceptibility to chagasic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Whole blood preparations from patients with either the indeterminate (asymptomatic) or cardiac clinical forms of chronic infection were analyzed by flow cytometry using double-labeling to identify subsets of circulating lymphocytes. Several significant differences were demonstrated between the blood lymphocyte profiles of chagaslc patients and non-chagaslc controls. Clear increase in the percentages and actual numbers of double-positive cells of the phenotype CD3/HLA-DR, as well as decrease in the percentage of CD45RA/CD4 and CD45RA/CD8 T cells, Indicate greater numbers of activated T cells circulating in the blood of infected patients. Consistent parallel increases were seen also in the B lymphocyte subset which stained double-positive for CD19/CD5. There were no significant differences in the circulation of these chronic chagaslc patients in the CD4:CD8 ratios. Also, no substantive phenotyplc differences were observed in the lymphocyte populations between the two ends of the clinical spectrum (Indeterminate versus cardiac) in chronic human Chagas' disease. These observations demonstrate that increased levels of activated T cells and CD5 B cells are present in the circulation of people with chronic Chagas' disease. These are cell phenotypes that have been associated in other conditions with autoimmune, polyclonal, and hyperlmmune responses. The specificities of these activated cells and the roles they may play in resistance or pathogenesis during chronic Chagas' disease need now to be determined. [ABSTRACT FROM PUBLISHER]

Chagas disease, caused by Trypanosoma cruzi, is a potentially life-threatening tropical disease endemic to Latin American countries that affects approximately 8 million people. In the chronic phase of the disease, individuals are classified as belonging to the indeterminate clinical form or to the cardiac and/or digestive forms when clinical symptoms are apparent. The relationship between monocytes and lymphocytes may be an important point to help clarify the complexity that surrounds the clinical symptoms of the chronic phase of Chagas disease. The co-stimulatory signals are essential to determining the magnitude of T cell response to the antigen. The signals are known to determine the regulation of subsequent adaptive immune response. However, little is known about the expression and function of these molecules in Chagas disease. Therefore, this review aims to discuss the possible role of main pathways of co-stimulatory molecule-receptor interactions in this pathology that could be crucial to understand the disease dynamics. [ABSTRACT FROM AUTHOR]

Increasing attention has been directed to cytotoxic CD4+ T cells (CD4CTLs) in different pathologies, both in humans and mice. The impact of CD4CTLs in immunity and the mechanisms controlling their generation, however, remain poorly understood. Here, we show that CD4CTLs abundantly differentiate during mouse infection with the intracellular parasite Trypanosoma cruzi. CD4CTLs display parallel kinetics to Th1 cells in the spleen, mediate specific cytotoxicity against cells presenting pathogen-derived antigens and express immunoregulatory and/or exhaustion markers. We demonstrate that CD4CTL absolute numbers and activity are severely reduced in both Myd88-/- and Il18ra-/- mice. Of note, the infection of mixed-bone marrow chimeras revealed that wild-type (WT) but not Myd88-/- cells transcribe the CD4CTL gene signature and that Il18ra-/- and Myd88-/-CD4+ T cells phenocopy each other. Moreover, adoptive transfer of WT CD4++GzB+ T cells to infected Il18ra-/- mice extended their survival. Importantly, cells expressing the CD4CTL phenotype predominate among CD4+ T cells infiltrating the infected mouse cardiac tissue and are increased in the blood of Chagas patients, in which the frequency of CD4CTLs correlates with the severity of cardiomyopathy. Our findings describe CD4CTLs as a major player in immunity to a relevant human pathogen and disclose T-cell intrinsic IL-18R/MyD88 signaling as a key pathway controlling the magnitude of the CD4CTL response. [ABSTRACT FROM AUTHOR]