Figure 2. Role of Tregs in immune-evasion of cancer after differentiation from the thymus. Natural Tregs, generated in the thymus, are initially differentiated from the thymocytes by using thymic “positive selection” based on the binding affinity of TCR to the self- peptides-MHC complexes expressed on thymic APCs. The CD4⁺ T cells which bind to self-peptide-MHC complexes with the highest affinity are removed through apoptosis, and those that cannot bind at all with the complexes will also be removed because of the absence of TCR stimulation. After strong TCR stimulation, these immature precursor cells undergo IL-2-mediated signaling, thus expressing the master transcription factor FOXP3, which orchestrates the differentiation of these cells into Tregs. By contrast, immature T cells with lower affinity for self-peptide–MHC complexes are also positively selected but differentiate into Teff cells. Even though some Teff cells are auto-reactive, Tregs can block the autoimmunity of Teff cells owing to their higher affinity. These immune cells that have departed from the thymus travel through the blood vessels and move wherever they are needed. In the tumor microenvironment, especially, Tregs expressing the chemokine receptors, such as CCR4, CCR5, CCR8, and CCR10, are recruited to and around the tumors by binding to chemokines including CCL1, CCL5, CCL22, and CCL28 that are secreted from various kinds of tumors. Moreover, Tregs constitutively express the IL-2 receptor subunit-α (also known as CD25) that binds to IL-2 with higher affinity, resulting in the depletion of IL-2 from their surroundings. This leads to the reduction of the availability of this cytokine to Teff cells. Tregs also constitutively express CTLA-4, a checkpoint protein suppressing the immune response, which binds to CD80 and CD86 on APC, thereby transmitting suppressive signals to Teff cells. In addition, Tregs secrete cytokines, such as IL-10, IL-35, and TGF-β, which can decrease the activity of APCs and Teff cells and secrete granzymes and perforins that can directly kill these cells. Moreover, abundant adenosine is produced by Tregs via nucleotidase activity of CD39 and CD73, which provides immunosuppressive signals to Teff cells and APCs through the engagement of adenosine A2AR.