Distinct CD4-CD8- (Double-Negative) Memory T-Cell Subpopulations Are Associated With Indeterminate and Cardiac Clinical Forms of Chagas Disease.

Livia Silva Araújo Passos,Carolina Cattoni Koh,Kenneth John Gollob,Walderez Ornelas Dutra,Luísa Mourão Dias Magalhães,Maria Do Carmo Pereira Nunes

doi:10.3389/fimmu.2021.761795

Abstract

CD4−CD8− (double-negative, DN) T cells are critical orchestrators of the cytokine network associated with the pathogenic inflammatory response in one of the deadliest cardiomyopathies known, Chagas heart disease, which is caused by Trypanosoma cruzi infection. Here, studying the distribution, activation status, and cytokine expression of memory DN T-cell subpopulations in Chagas disease patients without cardiac involvement (indeterminate form—IND) or with Chagas cardiomyopathy (CARD), we report that while IND patients displayed a higher frequency of central memory, CARD had a high frequency of effector memory DN T cells. In addition, central memory DN T cells from IND displayed a balanced cytokine profile, characterized by the concomitant expression of IFN-γ and IL-10, which was not observed in effector memory DN T cells from CARD. Supporting potential clinical relevance, we found that the frequency of central memory DN T cells was associated with indicators of better ventricular function, while the frequency of effector memory DN T cells was not. Importantly, decreasing CD1d-mediated activation of DN T cells led to an increase in IL-10 expression by effector memory DN T cells from CARD, restoring a balanced profile similar to that observed in the protective central memory DN T cells. Targeting the activation of effector memory DN T cells may emerge as a strategy to control inflammation in Chagas cardiomyopathy and potentially in other inflammatory diseases where these cells play a key role.

Highlights

The generation and maintenance of immunological memory is fundamental to preserve protective immune responses capable of controlling pathogens and of immune surveillance [1, 2]
Indeterminate patients (IND) displayed a higher percentage of central memory and naive DN T cells in T-cell receptors (TCR) ab+ and TCR gd+ subpopulations as compared with CARD, especially after TRP stimulation (Figure 1B)
Unsupervised Tdistributed stochastic neighbor-embedding (t-SNE) analysis clearly confirmed the predominance of central memory and naive in IND and of effector memory and effector DN T cells in CARD, especially after parasite stimulation (Figure 1C)

Summary

INTRODUCTION

The generation and maintenance of immunological memory is fundamental to preserve protective immune responses capable of controlling pathogens and of immune surveillance [1, 2]. The functional characteristics of DN T cells have been studied in patients with Chagas disease [13, 18, 21], which is a longlasting chronic infection caused by the protozoan Trypanosoma cruzi. We employed multiparameter flow cytometry to determine the distribution, activation, and cytokine profile of DN T cells from indeterminate and cardiac patients with Chagas disease. We performed in vitro blocking assays to show that manipulation of DN T-cell activation can be a useful strategy to modify EM cells toward a less inflammatory profile in Chagas cardiomyopathy patients. Cells were infected with 10 TRPs/cell, cultured in TABLE 1 | Chagas disease patients enrolled in the study.

RESULTS

DISCUSSION

ETHICS STATEMENT