Regulatory T-Cells: Diverse Phenotypes Integral to Immune Homeostasis and Suppression

Regulatory T-cells (T-REG) are diverse populations of lymphocytes that regulate the adaptive immune response in higher vertebrates. T-REG delete autoreactive T-cells, induce tolerance, and dampen inflammation. T-REG cell deficiency in humans (i.e., IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome]) and animal models (e. g., Scurfy mouse) is associated with multisystemic autoimmune disease. T-REG in humans and laboratory animal species are similar in type and regulatory function. A molecular marker of and the cell lineage specification factor for T-REG is FOXP3, a forkhead box transcription factor. CD4(+) T-REG are either natural (nT(REG)), which are thymus-derived CD4(+)CD25(+)FOXP3(+) T-cells, or inducible (i.e., Tr1 cells that secrete IL-10, Th3 cells that secrete TGF-beta and IL-10, and Foxp3(+) Treg). The proinflammatory Th17 subset has been a major focus of research. T(H)17 CD4(+) effector T-cells secrete IL-17, IL-21, and IL-22 in autoimmune and inflammatory disease, and are dynamically balanced with T-REG cell development. Other lymphocyte subsets with regulatory function include: inducible CD8(+) T-REG, CD3(+)CD4(-)CD8(-) T-REG (double-negative), CD4(+)V alpha 14(+) (NKTREG), and gamma delta T-cells. T-REG have four regulatory modes of action: secretion of inhibitory cytokines (e. g., IL-10 and TGF-beta), granzyme-perforin-induced apoptosis of effector lymphocytes, depriving effector T-cells of cytokines leading to apoptosis, or inhibition of dendritic cell function. The role of T-REG in mucosal sites, inflammation/infection, pregnancy, and cancer as well as a review of T-REG as a modulatory target in drug development will be covered.