The immune system uses a complex network of interacting cells that work together to regulate tissue physiology, homeostasis, and repair. In muscle, a tightly coordinated network of immunocytes and mesenchymal stromal cells (MSCs) is required for adequate skeletal muscle repair after acute injury or disease. Regulatory T cells (Tregs) are important players in regulating excessive inflammation and potentiating regeneration, but the extent of intercellular communications underlying their functions remains poorly understood. In this seminar, I will discuss my efforts in developing systems immunology approaches to dissect the dynamic communication networks between muscle Tregs and MSCs in a time-resolved study of skeletal muscle injury. Bringing together tools from single-cell and computational biology, engineering, and immunology, we uncovered distinct communication pathways important for the recruitment and induction of regenerative Tregs and the potentiation of muscle repair. This work identifies novel regulatory pathways that can inform therapeutic approaches for muscle-related pathologies.