Regulatory T Cells: Pathophysiological Roles and Clinical Applications

Abstract

Inflammation and immune responses after tissue injury play pivotal roles in the resolution of inflammation, tissue recovery, fibrosis, and remodeling. Regulatory T cells (Tregs) are responsible for immune tolerance and are usually activated in secondary lymphatic tissues. Activated Tregs subsequently regulate effector T cell and dendritic cell activation. For clinical applications such as the suppression of both autoimmune diseases and the rejection of transplanted organs, methods to generate stabilized antigen-specific Tregs are required. For this purpose, transcriptional and epigenetic regulation of Foxp3 expression has been investigated. In addition to conventional Tregs, there are some Tregs that reside in tissues and are called tissue Tregs. Tissue Tregs exhibit tissue-specific functions that contribute to the maintenance of tissue homeostasis and repair. Such tissue Tregs could also be useful for Treg-based cell therapy. We recently discovered brain Tregs that accumulate in the brain during the chronic phase of ischemic brain injury. Brain Tregs resemble other tissue Tregs, but are unique in expressing neural cell-specific genes such as the serotonin receptor (Htr7); consequently, brain Tregs respond to serotonin. Here, we describe our experiences in the use of Tregs to suppress graft-versus-host disease and to promote neural recovery after stroke.

Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection

“…Methylation of the foxp3 gene has an essential role in transcription of the gene, which further translates to cell phenotype and activity [68] . We thus evaluated the methylation status of the six regulatory regions of the foxp3 gene in FACS-sorted CD4 + FoxP3 + cells ( Supplementary Fig.…”

Regulatory T cells in ischemic stroke

“…16 Tregs may proliferate on the ischemic hemisphere side 7 days after tMCAO, indicating a possible kinetic delay in the adaptive immune response. 16,18,19 The increase of brain Tregs was significantly higher in aged male mice than in females at 15 days after tMCAO, indicating that the immune response of brain T cells may be time-specific and gender-specific. 20 In contrast to these findings, Kleinschnitz et al found a marked increase of Foxp3 + Tregs in the brain within 24 hours after tMCAO, but predominantly in the cerebral vasculature.…”

“…On day 14 after stroke, 40% of CD4 + T cells were Foxp3 + Tregs, which were recruited in and around the infarct area, and their number persistently increased and remained at a high level for 2 months 16 . Tregs may proliferate on the ischemic hemisphere side 7 days after tMCAO, indicating a possible kinetic delay in the adaptive immune response 16,18,19 . The increase of brain Tregs was significantly higher in aged male mice than in females at 15 days after tMCAO, indicating that the immune response of brain T cells may be time‐specific and gender‐specific 20 .…”

“…Rapamycin promotes Tregs to express higher levels of Foxp3 and CD25, allowing them to more strongly inhibit neuroinflammatory caused by macrophages and microglia 24 . Serotonin or selective serotonin reuptake inhibitor (SSRI) can increase the number of brain Tregs by acting on serotonin receptors, enhance their suppression function and improve neurological symptoms 19,90,91 . Hyperforin may induce Treg infiltration into the ischemic hemisphere as well as promote neuroangiogenesis and neurological function recovery, depending on IL‐6 secreted by astrocytes 92 .…”

“…24 Serotonin or selective serotonin reuptake inhibitor (SSRI) can increase the number of brain Tregs by acting on serotonin receptors, enhance their suppression function and improve neurological symptoms. 19,90,91 Hyperforin may induce Treg infiltration into the ischemic hemisphere as well as promote neuroangiogenesis and neurological function recovery, depending on IL-6 secreted by astrocytes. 92 Atorvastatin can enhance the inhibitory function of Tregs, induce Tregs migration to inflammatory tissue, 93 as well as downregulate the activation of microglia and astrocytes.…”