Fig. 3. Cell-based therapies for the induction of graft tolerance. Regulatory T cells (Tregs) inhibit the activation of effector T cells and antigen-presenting cells (APCs). A high level of high-affinity interleukin (IL)-2 receptor on Tregs prevents the use of IL-2 by effector T cells. The interaction of cytotoxic T lymphocyte antigen-4 (CTLA-4) on Tregs with CD80/86 on effector T cells and APCs inactivates the latter. CD39 and CD73 on Tregs produce the anti-inflammatory factor adenosine from ATP and 5'-adenosine monophosphate (5’-AMP). Tregs secrete granzyme B to induce the apoptosis of effector T cells [22,95]. Tregs produce transforming growth factor (TGF)-β and IL-10. TGF-β induces apoptosis of CD4+ T cells and suppresses the function of CD8+ T cells; IL-10 suppresses the activity of T helper 17 cells. Tregs interact with PD-L1 and PD-L2 on the surface of T cells via PD-1 to inhibit T cell responses. The transfer of cyclic adenosine monophosphate (cAMP) to T cells through intercellular gap junctions inhibits their activation. Tregs transfer miRNAs into T cells via exosomes [64]. Lymphocyte activation gene-3 (LAG-3) on Tregs binds to major histocompatibility complex (MHC) Ⅱ and inhibits antigen presentation by APCs. IL-10 downregulates their expression of MHC Ⅱ and costimulatory molecules. Granzyme B from Tregs induces the apoptosis of APCs. Inducible nitric oxide synthase (iNOS) in myeloid-derived suppressor cells (MDSCs) consumes L-arginine to produce nitric oxide (NO), preventing the use of the former by T cells to proliferate. In addition, arginase 1 (ARG1) produced by MDSCs cleaves L-arginine to ornithine and urea, preventing the use of the former by T cells. The production of a large quantity of heme oxygenase-1 (HO-1) by MDSCs contributes to the inactivation of T cells. CCL5 produced by MDSCs recruits Tregs from secondary lymphoid organs to grafts, where they induce tolerance. The interaction of B7-H1 (PD-L1) on MDSCs with PD-1 on Tregs promotes the migration, proliferation, and function of the latter. In the presence of interferon-γ, MDSCs produce IL-10 and TGF-β, which trigger the activation of Tregs [22]. Indoleamine 2,3-dioxygenase (IDO) on MDSCs consumes tryptophan and promotes kynurenine production. Tryptophan deficiency and excessive kynurenines suppress lymphocyte responses [96,97].
Clin Transplant Res 2024;38:309~325 https://doi.org/10.4285/ctr.24.0058