The effect of exercise on regulatory T cells: A systematic review of human and animal studies with future perspectives and methodological recommendations

Abstract

Many of the exercise-related health-promoting effects are attributed to beneficial immunomodulation. The restoration of immune homeostasis is context-dependent, meaning either to increase anti-inflammatory signaling to counteract disease progression of non-communicable (auto)inflammatory diseases or to enhance (local) activity of proinflammatory immune cells to slow down or inhibit cancer progression. Regulatory CD4+ T cells (T regs) represent the main regulatory component of the adaptive immune system that fine-tunes inflammatory responses, keeps them in check and prevents long-lasting autoimmunity. Because often dysregulated in the context of various diseases, emerging treatment approaches aim to modulate their number or inherent anti-inflammatory and immunosuppressive function in a highly disease-specific way. Exercise represents a non-pharmacologic strategy in disease prevention and rehabilitation and may be an effective treatment with few to no side effects to counteract dysregulation of T regs. To date, several studies have evaluated the effect of exercise on T reg-related outcomes. This review aims at providing a comprehensive overview on alterations of blood- or tissue-derived T reg counts, proportion and functionality following acute and chronic exercise in humans and animal models. From the 60 reviewed studies, an overall disease-specific beneficial effect of chronic exercise on T reg levels in animal models can be stated, while both acute and chronic effects in human studies are less definite. However, T reg phenotyping is less sufficient in the animal studies compared to human studies. Only a limited number of studies investigated T reg functionality. There is a large heterogeneity concerning study design, human population or animal model, exercise protocol, and T reg outcome measure specification which makes it difficult to compare results and draw clear conclusions. Study results are discussed in the context of current concepts in exercise immunology. Finally, future perspectives and methodological recommendations are provided to promote research in this field.