Inhibitory Receptors Are Expressed by Trypanosoma cruzi-Specific Effector T Cells and in Hearts of Subjects with Chronic Chagas Disease

Abstract

We had formerly demonstrated that subjects chronically infected with Trypanosoma cruzi show impaired T cell responses closely linked with a process of T cell exhaustion. Recently, the expression of several inhibitory receptors has been associated with T cell dysfunction and exhaustion. In this study, we have examined the expression of the cytotoxic T lymphocyte antigen 4 (CTLA-4) and the leukocyte immunoglobulin like receptor 1 (LIR-1) by peripheral T. cruzi antigen-responsive IFN-gamma (IFN-γ)-producing and total T cells from chronically T. cruzi-infected subjects with different clinical forms of the disease. CTAL-4 expression was also evaluated in heart tissue sections from subjects with severe myocarditis. The majority of IFN-γ-producing CD4+ T cells responsive to a parasite lysate preparation were found to express CTLA-4 but considerably lower frequencies express LIR-1, irrespective of the clinical status of the donor. Conversely, few IFN-γ-producing T cells responsive to tetanus and diphtheria toxoids expressed CTLA-4 and LIR-1. Polyclonal stimulation with anti-CD3 antibodies induced higher frequencies of CD4+CTAL-4+ T cells in patients with severe heart disease than in asymptomatic subjects. Ligation of CTLA-4 and LIR-1 with their agonistic antibodies, in vitro, reduces IFN-γ production. Conversely, CTLA-4 blockade did not improved IFN-γ production in response to T. cruzi antigens. Subjects with chronic T. cruzi infection had increased numbers of CD4+LIR-1+ among total peripheral blood mononuclear cells, relative to uninfected individuals and these numbers decreased after treatment with benznidazole. CTLA-4 was also expressed by CD3+ T lymphocytes infiltrating heart tissues from chronically infected subjects with severe myocarditis. These findings support the conclusion that persistent infection with T. cruzi leads to the upregulation of inhibitory receptors which could alter parasite specific T cell responses in the chronic phase of Chagas disease.

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

“…Accordingly, the increased expression of inhibitory receptors on CD8 + T cells from patients with severe disease could be implicated in the alteration of CD8 + T cell function. Consistently, in Chagas disease, although the levels of CD8 + T cells expressing the inhibitory receptor LIR-1 did not differ between chagasic patients and healthy volunteers, LIR-1 expression was found to increase with increasing disease severity (87). In contrast, the frequency of CD8 + T cells expressing CTLA-4 was lower, regardless of the disease severity.…”

“…As the parasite persists at low levels, the expression of inhibitory receptors on T cells is maintained during the early chronic stage (Fig. 6) (87). Thus, we propose the following scenario: in asymptomatic donors (group A), the CD8 + T cell profile is balanced, but the presence of the parasite induces polyfunctional CD8 + T cells, as observed in patients with mild disease (group B).…”

Presence of Antigen-Experienced T Cells with Low Grade of Differentiation and Proliferative Potential in Chronic Chagas Disease Myocarditis

“…Whereas most circulating IFN-γ-producing CD8 + and CD4 + T cells responsive to T. cruzi display a low degree of differentiation (CD27 + /CD28 + /CD57 − /LIR-1 − ) [8], [16], high differentiated (CD27 − /CD28 − /CD57 + /LIR-1 + ) CD8 + and CD4 + T cells are increased in the total peripheral T cell compartment of patients with severe cardiomyopathy [8], [15]–[17]. Subjects with chronic T. cruzi infection with severe cardiomyopathy also displayed lower frequencies of T. cruzi -responsive IFN-γ-producing T cells and lower levels of IFN-γ production compared to subjects with no signs of heart disease [8], [13], [16], leading us to propose that long-term parasite persistent might dampen parasite specific T cell responses [44]. Thus, recently developed effector T cells that bear a low degree of differentiation appear to be an important source of T. cruzi -specific T cells in the periphery of chronic Chagas disease patients.…”

Control of Chronic Mycobacterium tuberculosis Infection by CD4 KLRG1− IL-2–Secreting Central Memory Cells

“…For CD4 T cells, the phenomenon is not nearly as well characterized and understood, but there are clear indications that immune regulation and functional exhaustion take place in a number of chronic infections (18)(19)(20)(21)(22). In animal models, ongoing TB infection has recently been reported to drive T cells into a stage of terminal differentiation (23).…”