Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America but cases are
increasing in non-endemic countries, becoming a global concern. It affects 6 million people and imposes a
major economic burden due to early mortality and physical disabilities. Disease progression, from symptomless
to severe, is linked to parasite heterogeneity and a variable host immune response. Development of robust
CD8+ T cell immunity is a key element of host resistance and T. cruzi persistence and chronic Chagas disease
has been associated to suboptimal CD8+ T cell responses. Despite this, the knowledge about pathways that
promote robust protective CD8+ T cell immunity to T. cruzi remains incomplete and for instance, the metabolic
hurdles faced by effector CD8+ T cells for expansion and differentiation have been barely explored. Also, the
progression of T. cruzi infection is thought to be significantly modulated by regulatory immune responses that
limit parasite-specific immunity as well as infection-associated immunopathology by mechanisms poorly
understood. In this context, defining how effector and regulatory pathways intertwined to allow the generation
of optimal cellular immunity against T. cruzi preserving of tissue homeostasis is crucial to understand Chagas
disease pathogenesis. In this direction, our published data showed that Treg cells became activated during T.
cruzi infection and acquired phenotypic attributes that markedly changed along the infection. Thus, Treg cells
acquired features linked to the regulation of type 1 responses and limited CD8+ T cell immunity during the
infection acute phase, likely delaying parasite control and favoring chronicity. In contrast, preliminary data
demonstrate that Treg cells with tissue repair ties, which were disfavored during the acute phase, accumulated
during the chronic phase in nonlymphoid tissues considered targets of T. cruzi and reduced tissue damage.
Altogether, our findings highlight numerous changes in the phenotypic and functional profile as well as main
location of specialized Treg cells in the transition from acute to chronic phase, suggesting that Treg cell roles
switch from deleterious to protective in the course of this infection. A comprehensive characterization of
phenotype, function and transcriptional program of Treg cells in different tissues, together with the
manipulation of this regulatory subset by different strategies will allow us to define the mechanisms underlying
Treg cell mediated regulation of effector immunity and immunopathology in acute and chronic experimental T.
cruzi infection. These approaches will guide our evaluation of effector and regulatory pathways and their
association to the clinical severity in samples of patients with chronic Chagas disease in order to translate our
finding to human health. Altogether, our studies will provide meaningful data about different interacting
pathways and, possibly, new mediators that participate in the regulation of effector cellular immunity to T. cruzi
and the development of chronic pathology. This information will identify potential new targets for the rational
design of therapies for Chagas´ disease and, likely, other chronic infections.