CD4+ T cells from chronica Chagas disease patients with different degrees of cardiac compromise exhibit distinct expression patterns of inhibitory receptors TIGIT, TIM-3 and LAG-3

Abstract

In the chronic stage of Chagas disease, patients show a high frequency of activated T cells. Despite this, persistent presence of antigenic stimulus may affect their functionality and induce an exhausted phenotype with a high expression of inhibitory receptors and loss of effector functions. We hypothesize that inhibitory receptors TIGIT, Tim-3 and Lag-3 may be involved in immune modulation of anti-T. cruzi T cell response.In the present work, we assessed the frequency of CD4+ T cells expressing these receptors and their relation to cellular activation, measured as the expression of activation induced markers (AIM) Ox40 and CD25. Samples from chronic Chagas disease patients (CCD) with different degrees of cardiac compromise (asymptomatic, A, and with cardiopathy, C) and non-infected donors (NI) were analyzed under different stimulation conditions: T. cruzi lysate (Tc), unstimulated, or PHA.We observed statistically significant differences in the frequency of activated (Ox40+CD25+) CD4+ T cells between the CCD and NI subjects when stimulated with Tc. Cells from CCD showed an increased frequency of CD4+TIGIT+ T cells upon stimulation with PHA as compared with the unstimulated condition. CD4+Tim-3+ T cells are more abundant in the circulation of C patients and Lag-3+ cells showed increased frequency in the non-activated subset, within the A group.We demonstrated that the AIM method can be used to detect anti-T.cruzi response in CD4+ T cells, upon in vitro stimulation with Tc. Also, TIGIT, Tim-3 and Lag-3 are expressed differently, or they behave in diverging ways upon in vitro stimulation, in CCD.