Pathogenic regulatory T cells promote immunopathology during infectious myositis

Abstract

Abstract Immune dysfunction is a central event in the pathogenesis of idiopathic inflammatory myopathies, yet its etiology remains elusive. Skeletal muscle repair is reliant on the temporally distinct transition from pro-inflammatory (M1) to pro-regenerative (M2) macrophage-mediated phases of repair. Regulatory T cells (Treg) facilitate this transition and its dysregulation results in debilitating disease. Infection of C57Bl/6 mice with Toxoplasma gondii is an ideal model to study perturbations of Treg as infection causes their systemic collapse and high levels of Th1 inflammation. During infection, we observe that M1 persist in skeletal muscle, which at steady state is dominated by M2. Skeletal muscle Treg frequencies dramatically decrease and become Th1-skewed. Therefore, we hypothesized that infection alters Treg function and their ability to promote M2 in skeletal muscle. To test the effect of chronic interferon-gamma (IFNγ) exposure on Treg function, we adoptively transferred Treg cultured with and without IFNγ. Surprisingly, adoptive transfer of IFNγ-Treg significantly increased M1 in infected skeletal muscle, while transfer of non-polarized Treg did not affect M1 or M2 numbers. Furthermore, systemic depletion of Treg in infected mice increased muscle fiber regeneration through increased M2:M1 ratios without an increase in inflammation or immunopathology. Collectively, we show T. gondii infection promotes pathogenic Treg in the skeletal muscle. As Treg-directed therapies gain traction, a deeper understanding of the consequences of chronic inflammation on Treg physiology and tissue-specific reparative programing will be a powerful asset in producing safe and efficacious therapies.