The role of regulatory T cells in central nervous system diseases in dogs: fighting with a double-edged sword toward translational discoveries.

Regulatory T cells (Tregs) are a recently discovered subpopulation of immunosuppressive T cells critical for sustaining immune homeostasis and self-tolerance. Depending on the disease, Tregs can alter immune responses by exerting their effects on various immunological functions. Evidence reveals that altered Treg homeostasis plays an important role in the development and progression of several central nervous system (CNS) diseases in humans. There have been positive outcomes in trials aimed at restoring Treg balance, but their clinical success has been limited. This could partly be due to a lack of an animal model to recapitulate the complex immune alterations that occur as the disease progresses. Therefore, there is a need for naturally occurring, immune-competent disease models to serve as the next critical step in translating therapy from murine models to human clinical trials. Several CNS diseases have canine analogs due to high inter-species homology of molecular signatures and clinicopathologic features. Human multiple sclerosis, Alzheimer's disease, glioblastoma, and meningioma parallel canine granulomatous meningoencephalomyelitis (GME), canine cognitive dysfunction (CCD), high-grade glioma (HGG), and canine meningioma, respectively. In addition, pet dogs share the same living environment and therefore may offer a compelling model faithfully recapitulating these diseases. This review discusses the current knowledge of Treg homeostasis and dysregulation mechanisms within canine CNS diseases, their analogous diseases in humans, and the ongoing clinical trials aimed at restoring normal Treg function. Collectively, comparative translational research investigating Treg homeostasis is needed to bridge well-designed pre-clinical canine studies with early-phase human clinical trials, ultimately benefiting the health of both species.