Circulating T Follicular Helper Cell Abnormalities Associated to Different Clinical Forms of Chronic Chagas Disease.

Luz P. Quebrada Palacio,Miriam Postan,Patricia B. Petray,Esteban R. Fernández,Yolanda Hernández-Vásquez

doi:10.3389/fcimb.2020.00126

Abstract

Multiple perturbations of the immune response affecting a range of cells have been reported in Trypanosoma cruzi-infected individuals and associated to clinical manifestations of chronic Chagas disease. There is a paucity of knowledge about the role of T follicular helper (Tfh) cells in this infection. Here, we sought to characterize circulating Tfh (cTfh) cells in chronic Chagas disease patients and to identify potential associations with disease severity in humans. cTfh cells were characterized by flow cytometry in freshly isolated PBMCs from 7 T. cruzi-infected asymptomatic patients (ASYMP), 5 patients with chronic chagasic dilated cardiomyopathy (CCC) and 8 healthy controls, using antibodies against chemokine receptors CXCR5, CXCR3, CCR6, and CCR7. Our results showed significant expansion of CD4+CD45RO+CXCR5+CCR6+ cells in ASYMP and CCC patients, along with a contraction of CD4+CD45RO+CXCR5+CXCR3-CCR6- (cTfh2) cells. ASYMP patients further exhibited decreased CD4+CD45RO+CXCR5+CXCR3+CCR6- (cTfh1) cells and expanded CD4+CD45RO+CXCR5+CXCR3-CCR6+ (cTfh17) cells while CCC patients exhibited significantly increased frequencies of CD4+CD45RO+CXCR5+CCR7+ cells. Linear regression analysis revealed a positive trend of CD4+CD45RO+CXCR5+CXCR3+CCR6+ (cTfh1/17) cells and negative trends of cTfh1 and cTfh2 cells as disease was more severe. There was no correlation between the frequencies of cTfh cells and circulating CD19+IgD-IgG+ cells or serum levels of T. cruzi-specific IgG. These results demonstrate that the cTfh compartment of humans chronically infected with T. cruzi comprises expanded CCR6-expressing cells and reduced cTfh2 cells. The association of discrete phenotypic changes in cTfh subsets with different clinical forms suggests the potential contribution of T follicular helper cells to Chagas heart disease progression.

Highlights

Trypanosoma cruzi, the etiological agent of Chagas disease, causes a broad spectrum of clinical outcomes, ranging from a mild, frequently asymptomatic acute illness with low mortality rate to a potentially life-threatening cardiomyopathy, digestive and/or neurological abnormalities in up to 30%of chronically infected individuals (WHO World HealthOrganization, 2018)
To determine whether T. cruzi infection leads to a change in the phenotype of circulating Tfh (cTfh) cells, we examined the expression of CCR7 and PD-1 (Sallusto et al, 1999; Keir et al, 2008)
We evaluated the expression of the chemokine receptors CXCR3 and CCR6 on CD4+CD45RO+CXCR5+ cells from patients chronically infected with T. cruzi

Summary

Introduction

Trypanosoma cruzi, the etiological agent of Chagas disease, causes a broad spectrum of clinical outcomes, ranging from a mild, frequently asymptomatic acute illness with low mortality rate to a potentially life-threatening cardiomyopathy, digestive and/or neurological abnormalities in up to 30%of chronically infected individuals (WHO World HealthOrganization, 2018). Trypanosoma cruzi, the etiological agent of Chagas disease, causes a broad spectrum of clinical outcomes, ranging from a mild, frequently asymptomatic acute illness with low mortality rate to a potentially life-threatening cardiomyopathy, digestive and/or neurological abnormalities in up to 30%. Several parasite proteins have been shown to promote parasite invasion, replication and survival (Watanabe Costa et al., 2016). These molecules might subvert the complement system and favor intracellular parasite growth, hampering the development of parasite-specific innate and adaptive immune responses (Cardoso et al, 2016). Several defects of the T cell compartment have been associated with the progression of asymptomatic T. cruzi infection to Chagas heart disease.

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