Expression and functionality of co-inhibitory receptors TIGIT, TIM-3 and LAG-3 in CD4+ T cells from patients with chronic Chagas disease

Abstract

Chagas disease, caused by Trypanosoma cruzi, affects 7 million people worldwide, mainly in Latin America where it is endemic. Unless treated early after infection, the disease progresses to a chronic form in which some patients develop cardiac or digestive alterations, while others stay asymptomatic. CD4+ T cell response plays critical and diverse roles during infection, and becomes impaired over time with defective cytokine release. This process known as T cell exhaustion is also defined by the upregulation of inhibitory receptors, mainly PD-1 and CTLA-4. In this work, we aimed to explore the expression of the second line of inhibitory receptors TIGIT, TIM-3 and LAG-3 in parasite stimulated CD4 T cells from patients with different stages of chronic Chagas disease (CCD), and whether their blockade restores cell functionality. Antigen-specific CD4 T cells were identified by activation induced markers (AIM) assay, using the surface molecules Ox40 and CD25. CCD patients, independently of their clinical stage, showed an increased frequency of CD4+TIGIT+ T cells. TIM-3+ CD4+ T cells were more abundant in patients with cardiac manifestations, while LAG-3+ cells were increased in asymptomatic CCD patients, with higher frequency within the non-activated cells subpopulation upon T. cruzi lysate stimulation. Preliminary data showed that TIM-3 blockade tended to increase IFN-g+ CD4+ T cells in CCD patients with cardiomyopathy. Furthermore, in the same group of subjects, the incubation with anti-TIGIT blocking antibody led to a greater frequency of IL-10+ CD4+ T cells compared to the isotype control antibody. Our results highlight the role of the inhibitory receptors TIGIT, TIM-3 and LAG-3 in the modulation of anti-T. cruzi CD4+ T cell responses, in relation with the progression of chronic Chagas disease, and paves the way for the development of novel therapeutic strategies.