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

Abstract

Regulatory T-cells (TREG) are diverse populations of lymphocytes that regulate the adaptive immune response in higher vertebrates. TREG delete autoreactive T-cells, induce tolerance, and dampen inflammation. TREG 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. TREG in humans and laboratory animal species are similar in type and regulatory function. A molecular marker of and the cell lineage specification factor for TREG is FOXP3, a forkhead box transcription factor. CD4+ TREG are either natural (nTREG), which are thymus-derived CD4+CD25+FOXP3+ T-cells, or inducible (i.e., Tr1 cells that secrete IL-10, Th3 cells that secrete TGF-β and IL-10, and Foxp3+ Treg). The proinflammatory Th17 subset has been a major focus of research. TH17 CD4+ effector T-cells secrete IL-17, IL-21, and IL-22 in autoimmune and inflammatory disease, and are dynamically balanced with TREG cell development. Other lymphocyte subsets with regulatory function include: inducible CD8+ TREG, CD3+CD4−CD8− TREG (double-negative), CD4+Vα14+ (NKTREG), and γδ T-cells. TREG have four regulatory modes of action: secretion of inhibitory cytokines (e.g., IL-10 and TGF-β), 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 TREG in mucosal sites, inflammation/infection, pregnancy, and cancer as well as a review of TREG as a modulatory target in drug development will be covered.