CTLA-4 Blockage Increases Resistance to Infection with the Intracellular Protozoan<i>Trypanosoma cruzi</i>

Martins, Gislâine A.; Tadokoro, Carlos E.; Silva, Roberta Borges; Silva, João; Rizzo, Luiz Vicente

doi:10.4049/jimmunol.172.8.4893

Cited by 49 publications

(49 citation statements)

References 62 publications

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“…In fact, the blockade of PD-1 and PD-L1 or deletion of the PD-1 gene ameliorated the control of parasite burden both systemically and in cardiac tissue. Similar to our current results, we previously reported that T. cruzi induces upregulated expression of another coinhibitor molecule, CTLA-4, in lymphocytes in vivo and in vitro, and the blockade of this inhibitory signaling pathway lead to increased inflammation and decreased tissue parasitism (23).…”

Section: Discussionsupporting

confidence: 80%

Regulation of Trypanosoma cruzi-Induced Myocarditis by Programmed Death Cell Receptor 1

et al. 2011

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Trypanosoma cruzi infection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction. Protective adaptive immunity depends on balanced signaling through a T cell receptor and coreceptors expressed on the T cell surface. Such coreceptors can trigger stimulatory or inhibitory signals after binding to their ligands in antigen-presenting cells (APC). T. cruzi modulates the expression of coreceptors in lymphocytes after infection. Deregulated inflammation may be due to unbalanced expression of these molecules. Programmed death cell receptor 1 (PD-1) is a negative T cell coreceptor that has been associated with T cell anergy or exhaustion and persistent intracellular infections. We aimed to study the role of PD-1 during T. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response to T. cruzi infection in vivo and in vitro. Lymphocytes infiltrating the myocardium exhibited high levels of expression of these molecules. An increased cardiac inflammatory response was found in mice treated with blocking antibodies against PD-1, PD-L1, and to a lesser extent, PD-L2, compared to that found in mice treated with rat IgG. Similar results in PD-1 ؊/؊ mice were obtained. Moreover, the PD-1 blockade/deficiency led to reduced parasitemia and tissue parasitism but increased mortality. These results suggest the participation of a PD-1 signaling pathway in the control of acute myocarditis induced by T. cruzi and provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas' disease.Chagas' disease is the most important cause of acquired cardiomyopathy in Latin America and is one of the outcomes resulting from the interaction between the human immune system and the hemoflagellate prokaryote Trypanosoma cruzi. In the natural infection, the flagellated forms in the feces of infected hematophagous insects of the Triatominae subfamily invade the host through skin lesions or intact mucosa. The parasite then proliferates intracellularly and disseminates systemically from the site of inoculation, causing an inflammatory reaction of variable intensity, along with splenomegaly, cardiac parasitism, and myocarditis, which is largely associated with morbidity. More frequently, a chronic asymptomatic infection is established, which eventually leads to dilated cardiomyopathy and heart failure as well as esophageal or intestinal dilatations due to the combined effects of parasite persistence, immune deregulation, autonomic denervation, and microvascular damages (21,30).The immunological mechanisms underlying this silent, relentless infection and heart pathology remain elusive despite several decades of research. It is known that T cell-mediated immune responses are essential to control the parasite replication during the acute phase of the infection (33). The cytokines gamma interferon (IFN-␥), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-␣) strengthen the activation of innate and adaptive ...

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Section: Discussionsupporting

confidence: 80%

Regulation of Trypanosoma cruzi-Induced Myocarditis by Programmed Death Cell Receptor 1

et al. 2011

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“…Previous studies have shown that CD28-deficient mice were highly susceptible to T. cruzi infection, presenting with higher parasitemia and tissue parasitism but less inflammation in the heart than those of wildtype mice (28). Moreover, it has been shown that modulation via CTLA-4 during the acute phase of experimental infection leads to a decreased ability to clear the parasite and, thus, susceptibility to T. cruzi infection (29). Our previous findings have shown that chagasic patients, despite their clinical form, showed decreased expression of CD28 by freshly isolated T cells compared to that of noninfected individuals (9,30).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have evaluated the role of costimulatory molecules in murine infection with T. cruzi. It has been shown that mice that are deficient in CD28 are highly susceptible to T. cruzi infection (28), whereas CTLA-4 blocking increases resistance to infection (29). In humans, it has been demonstrated that chagasic patients have a higher frequency of CD28 Ϫ T cells in their bloodstream and that these cells display a heterogeneous repertoire (9,30).…”

mentioning

confidence: 99%

Trypanosoma cruziInfection Induces Differential Modulation of Costimulatory Molecules and Cytokines by Monocytes and T Cells from Patients with Indeterminate and Cardiac Chagas' Disease

et al. 2007

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Interactions between macrophages and lymphocytes through costimulatory molecules and cytokines are essential for mounting an efficient immune response and controlling its pathogenic potential. Here we demonstrate the immunomodulatory capacity of Trypanosoma cruzi, the causative agent of Chagas' disease, through its ability to induce differential expression of costimulatory molecules and cytokines by monocytes and T cells. Costimulatory molecule and cytokine modulation was evaluated using cells from noninfected individuals and from patients with the asymptomatic indeterminate form and those with the severe cardiac clinical form of Chagas' disease. Our results show that while exposure of monocytes to live T. cruzi leads to an increase in the frequency of CD80 ؉ monocytes in all groups, it decreases both the frequency and intensity of CD86 expression by monocytes from patients with the cardiac form but not from those with the indeterminate form. Conversely, exposure of lymphocytes to monocytes infected with T. cruzi increased the surface expression of cytotoxic-Tlymphocyte-associated antigen 4 (CTLA-4) by T cells from indeterminate but not from cardiac patients, compared to that from control patients. These data suggest that T. cruzi induces a potentially down-regulatory environment in indeterminate subjects, which is associated with higher CD80 and CTLA-4 expression. To test the functional importance of this modulation, we evaluated the expression of cytokines after in vitro infection. Although exposure of lymphocytes to parasite-infected monocytes induced high expression of inflammatory and anti-inflammatory cytokines by T cells in all groups, indeterminate patients displayed a higher ratio of monocytes expressing interleukin 10 than tumor necrosis factor alpha following infection than did controls. These data show the ability of T. cruzi to actively change the expression of costimulatory molecules and cytokines, suggesting molecular mechanisms for the differential clinical evolution of human Chagas' disease.

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“…Although inhibitory receptor expression on T cells is an indicator of Ag elimination failure, these receptors are important for self-tolerance and the prevention of autoimmunity (12). The increased expression of CTLA-4 and PD-1 in lymphocytes has been described in acute T. cruzi mouse infection, and as expected (15,(88)(89)(90), the blockade of these inhibitory receptors decreases parasitemia and parasitism and increases inflammation and mortality (91,92). In this article, we report increased inhibitory receptor expression on CD8 + T cells in patients with severe forms of the disease, which, consistent with other chronic infections (12), could be implicated in the alteration of CD8 + T cell polyfunctionality.…”

Section: Cd8mentioning

confidence: 99%

Inhibitory Receptor Expression on CD8+ T Cells Is Linked to Functional Responses against Trypanosoma cruzi Antigens in Chronic Chagasic Patients

Lasso

Mateus

Pavía

et al. 2015

The Journal of Immunology

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In mammals, chronic diseases resulting from infectious agents have been associated with functional T cell response deficiency, a high frequency of terminally differentiated T cells, the presence of monofunctional Ag-specific T cells, and increased expression of inhibitory receptors. Similar to other chronic diseases, the progressive loss of certain functional activities during Trypanosoma cruzi infection might result in the inability to control replication of this parasite. To examine this hypothesis, we evaluated the differentiation and cell effector function of CD8+ T cells and characterized the expression of inhibitory receptors and the presence of the parasite in the bloodstream of chagasic patients. The results showed that patients at an advanced severe disease stage had a higher frequency of terminally differentiated CD8+ T cells than patients at an early stage of the disease. A monofunctional CD8+ T cell response was observed in patients at an advanced stage, whereas the coexpression of markers that perform three and four functions in response to parasite Ags was observed in patients at a less severe disease stage. The frequency of CD8+ T cells producing granzyme B and perforin and those expressing inhibitory receptors was higher in symptomatic patients than in asymptomatic patients. Taken together, these findings suggest that during the course of Chagas disease, CD8+ T cells undergo a gradual loss of function characterized by impaired cytokine production, the presence of advanced differentiation, and increased inhibitory receptor coexpression.

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CTLA-4 Blockage Increases Resistance to Infection with the Intracellular ProtozoanTrypanosoma cruzi

Cited by 49 publications

References 62 publications

Regulation of Trypanosoma cruzi-Induced Myocarditis by Programmed Death Cell Receptor 1

Regulation of Trypanosoma cruzi-Induced Myocarditis by Programmed Death Cell Receptor 1

Trypanosoma cruziInfection Induces Differential Modulation of Costimulatory Molecules and Cytokines by Monocytes and T Cells from Patients with Indeterminate and Cardiac Chagas' Disease

Inhibitory Receptor Expression on CD8+ T Cells Is Linked to Functional Responses against Trypanosoma cruzi Antigens in Chronic Chagasic Patients

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