Mechanisms and control of regulatory T cells in cancer

CD4+ regulatory T (Treg) cells play an important role in mediating immune-suppression to prevent autoimmune diseases. Depletion of Treg cells in normal hosts results in various types of autoimmune diseases because the host immune system is unchecked, and progresses to attack the body's own tissues or organs. Despite the importance of these cells in preventing autoimmune diseases, their accumulation in the tumor microenvironment dampens antitumor immune responses and may, at least in part, explain why current clinical trials with cancer peptides or dendritic cells (DCs) pulsed with antigenic peptides can induce only weak and-transient immune responses, and fail to produce therapeutic efficacy of cancer-treatment. Besides naturally occurring Treg cells, many subsets of Treg cells have been identified, including inducible CD4+ Treg cells, CD8+ Foxp3+ Treg, and γδ+ TCR Treg cells in cancer patients. Foxp3 is a master regulator of Treg cells; its expression is critically controlled by many factors including TCR signaling, and cytokines such as TGF-β and IL-2. Understanding of the molecular mechanisms and strategies which modulate regulatory function of Treg cells has been an important research area for both basic and clinical application, where the goal is to treat and prevent immune-related diseases and cancer. In this review, we highlight recent advances in our understanding of subsets, immune regulation of Treg cells, Foxp3 expression, and discuss important implications for cancer immunotherapy.