Dual Th1 and tissue-repair Treg cells accumulate in skeletal muscle preserving tissue integrity during infection

Abstract

Chronic infections require mechanisms that limit tissue damage while preserving pathogen control, yet the contribution of regulatory T (Treg) cells to this balance remains unclear. In this study, we characterized Treg cell responses during a chronic parasitic infection using experimental Trypanosoma cruzi infection as a model of persistent low-level parasitism and chronic tissue inflammation. We found that, although Treg cell numbers decline in the spleen, they accumulate in parasite-affected tissues such as skeletal muscle, where they adopt a combined Th1-associated and tissue-repair program. Systemic Treg cell depletion had limited impact on immune and disease-associated parameters, whereas local depletion in skeletal muscle exacerbated tissue damage and increased parasite burden. Moreover, transient systemic perturbation of Treg cells during the acute phase impaired their long-term accumulation in skeletal muscle, resulting in increased tissue damage and parasite burden during chronic infection. Additionally, accumulation of reparative Treg cells in skeletal muscle was impaired in the absence of ST2. Together, these findings identify a tissue-adapted Treg cell population that integrates inflammatory and reparative programs to preserve skeletal muscle integrity during chronic parasitic infection. SUMMARYChronic parasite infection drives the emergence of tissue-adapted regulatory T cells that integrate Th1-associated and tissue-repair programs. These cells accumulate in skeletal muscle, where they preserve tissue integrity while contributing to microbial control, highlighting the dynamic specialization of Treg cells across disease stages.