Being the focus of the 2025 Nobel Prize in Physiology or Medicine awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi, the critically important CD4 + CD25 + FOXP3 + regulatory T cells (Tregs) provide an array of functions that provide homeostasis to the immune response. Examples of their immunosuppressive functions include the production of inhibitory cytokines (interleukin-10 IL-10, IL-35, and active transforming growth factor β) and the downregulation of antigen presentation (via physical blockade and trogocytosis of co-stimulatory ligands and major histocompatibility complex class II). 1 Also fundamental to the Treg subset is the sustained expression of the high-affinity IL-2Rαβγ complex. While conventional T (Tconv) cells express the β- and γ-subunits at steady state, IL-2Rα, also known as CD25, provides Tregs with the superior ability to bind the T cell-activating cytokine IL-2. Unlike Tconv cells, which only upregulate CD25 upon stimulation, Tregs constitutively express CD25. Moreover, in contrast to Tconv cells, Tregs do not secrete IL-2 upon stimulation. This allows for Tregs to function as a cytokine “sink” that disrupts the adaptive immune cascade by interfering with the IL-2 autocrine signaling of activated T cells. The importance of this CD25-dependent function is also evident in mice, where germline knockouts manifest into systemic autoimmunity, likely due to Treg dysfunction. In humans, mutations in the CD25 gene have been correlated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, in part because Tregs’ inability to sequester IL-2 results in varying degrees of immune dysfunction. 2
Brim et al. (Sun,) studied this question.