Internal peacekeepers and external mediators: A new model of peripheral immune tolerance involving regulatory T cells and mesenchymal stem cells.

The 2025 Nobel Prize in Physiology or Medicine honored the seminal discovery that regulatory T cells (Tregs) restrain immune responses and prevent autoimmunity through peripheral immune tolerance. However, to obtain a holistic view of peripheral immune tolerance, it is also necessary to consider the role of mesenchymal stem/stromal cells (MSCs) in this process. Therefore, I propose a two-tier model that incorporates both Tregs and MSCs, with Tregs acting within the immune system as an "internal checkpoint" to temper effector cell activity, and tissue-resident MSCs - or "master signaling cells" - serving as an "external checkpoint." Injuryor pathogen-induced inflammation activates MSCs, which in turn secrete a broad repertoire of immunomodulatory molecules, create a local anti-inflammatory milieu, promote tissue repair, and directly dampen excessive immune activity at the site of damage. The concerted actions of Tregs and MSCs are essential for effective peripheral immune tolerance, shielding the host from pathogens and collateral tissue injury. This model helps explain the pathophysiology of autoimmunity and tumor immune evasion, as well as the therapeutic potential of MSC-based interventions.