Fig. 4: Mechanisms of Treg suppression.
Regulatory T cells (Treg) suppress conventional T cells (Tconv) through different mechanisms, divided into contact-mediated or cytokine-mediated. All mechanisms demonstrate suppressive mechanisms validated in human Tregs, except for mechanisms that are in gray and not bolded. Contact-mediated suppression includes (i) Transforming growth factor beta (TGFβ) tethered to the surface of Tregs through Glycoprotein A Repetitions Predominant (GARP), which is activated upon physical contact with Tconvs63. (ii) CD95 can bind to CD95L on Tconv to induce apoptosis153. (iii) Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) can bind to CD80 on Tconv cells to prevent co-stimulation or can bind to antigen-presenting cells to prevent CD28 from binding through trans-endocytosis130,154. (iv) LAG3 (lymphocyte activating 3) can inhibit major histocompatibility complex (MHC) II signaling through direct binding155. Cytokine-mediated suppression includes i) ATP hydrolysis to adenosine through CD3957. (ii) TGFβ signaling in an autocrine fashion to maintain Forkhead Box Protein P3 (FOXP3) expression62 or binding to Tconv to induce FOXP3 expression when co-stimulated with IL-261. (iii) IL-10 released by Tregs binds to IL-10 receptor (IL10R) on Tconv cells to convert to T-regulatory 1 cells (TR1)66 or binds to IL10R on dendritic cells to downregulate function. iv)Absorption of IL-2 through CD25 to prevent absorption by Tconv and limit proliferation60. (v) Apoptosis of Tconv cells through the release of Galactin-1156 or lysis of Tconv after releasing granzymes. (iv) Although human Tregs were found not to express IL-35 like murine Tregs157, IL-35 stimulation can enhance suppression by inducing conventional T cells to express IL-35158. IL, interleukin; CD, Cluster of Differentiation. The figure was created in BioRender. Pacheco, A. (2026) https://BioRender.com/xo88hoh.
