Antigen-Specific T Cells Maintain an Effector Memory Phenotype during Persistent Trypanosoma cruzi Infection

Abstract

Infection with the protozoan parasite Trypanosoma cruzi is a major cause of morbidity and mortality in Central and South America. Control of acute experimental infection with T. cruzi is dependent on a robust T cell and type 1 cytokine response. However, little evidence exists demonstrating the development and persistence of a potent antiparasite T cell memory response, and there has been much speculation that the majority of the immune response to T. cruzi infection is not directed against the parasite. In this study, we used an experimental mouse model of T. cruzi infection to test both the Ag specificity and the functional and phenotypic characteristics of the responding T cell population. We observed a vigorous antiparasite response from both CD4+ and CD8+ T cells that was maintained in the face of persistent infection. T cells from infected mice also proliferated in response to re-exposure to Ag, and CD8+ T cells underwent spontaneous proliferation when transferred to naive congenic mice, both characteristic of central memory T cells. Interestingly, T cells from infected mice showed significant down-regulation of CD62L, a characteristic associated with an effector memory phenotype. These results suggest that T cells maintained in mice with chronic T. cruzi infection are fully functional memory cells that cannot be easily categorized in the current central/effector memory paradigm.

TGF‐β regulates pathology but not tissue CD8+ T cell dysfunction during experimental Trypanosoma cruzi infection

“…Single-cell suspensions of splenocytes from uninfected or T. cruzi-infected mice were generated as previously described [35]. Muscle-derived lymphocytes were obtained by teasing tissues apart and vigorously pushing through a 40-lm nylon mesh screen, followed by extensive washing with RPMI-10.…”

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

“…Although this process was initially described for models of chronic viral infections, such as lymphocytic choriomeningitis, HIV, simian immunodeficiency, and HBV and HCV (12), recent studies have shown that this phenomenon also occurs in protozoan infections (65,66). Chagas disease is associated with a poor functional T cell response and is characterized by increased levels of terminally differentiated T cells and monofunctional Ag-specific T cells (24)(25)(26)28). Thus, the aim of this study was to determine whether CD8 + T cells lose polyfunctionality with an advanced stage of cell differentiation and sustained inhibitory receptor expression during CCD.…”

“…In addition, it has been shown that CD8 + T cell proliferation is diminished in chronic chagasic patients (CCP) compared with healthy donors (HD) and patients with nonchagasic cardiomyopathy (27). Moreover, an increase in the frequency of fully differentiated CD8 + T cells with attenuated cytokine effector functions has been observed in subjects presenting a severe form of this disease and in mouse models of chronic Chagas disease (CCD) (25,28,29). These data suggest that, similar to other chronic infections (16)(17)(18)(19), CD8 + T cells undergo a progressive dysfunction during T. cruzi infection that is characterized by impaired functional activity, advanced cell differentiation, and increased inhibitory receptor coexpression.…”

Insufficient TLR Activation Contributes to the Slow Development of CD8+ T Cell Responses in Trypanosoma cruzi Infection

“…Spleens and draining lymph nodes were mechanically disrupted, and single cell suspensions were stained with TSKB20/K b tetramer as previously described (4) or were stimulated overnight with 1 M of TSKB20 peptide and processed with a Cytofix/Cytoperm kit (BD Pharmingen) and stained to detect IFN-␥ production in accordance with the manufacturer's instructions and as previously described (8).…”