Peripheral and Thymic Foxp3+ Regulatory T Cells in Search of Origin, Distinction, and Function

Abstract

Over the past decade, much has been learnt and much more to discover about Foxp3+ regulatory T cells (Tregs). Initially, it was thought that Tregs were a unique entity that originates in the thymus. It is now recognized that there is a fraternal twin sibling that is generated in the periphery. The difficulty is in the distinction between these two subsets. The ability to detect, monitor, and analyze these two subsets in health and disease will provide invaluable insights into their functions and purposes. The plasticity and mechanisms of action can be unique and not overlapping within these subsets. Therefore, the therapeutic targeting of a particular subset of Tregs might be more efficacious. In the past couple of years, a vast amount of data have provided a better understanding of the cellular and molecular components essential for their development and stability. Many studies are implicating their preferential involvement in certain diseases and immunologic tolerance. However, it remains controversial as to whether any phenotypic markers have been identified that can differentiate thymic versus peripheral Tregs. This review will address the validity and controversy regarding Helios, Lap/Garp and Neuropilin-1 as markers of thymic Tregs. It also will discuss updated information on distinguishing features of these two subsets and their critical roles in maternal-fetal tolerance and transplantation.

Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease

“…Although Nrp-1 was initially proposed as a naturally occurring T reg -cell-specific marker (14,17), additional studies have shown that peripherally induced T reg cells are capable of up-regulating Nrp-1, especially in the lung (18,19). Consequently, it remains uncertain whether the expanded T reg cells in the lungs of BeOexposed HLA-DP2 Tg mice are naturally occurring or peripherally induced.…”

Helios Expression in T-regulatory Cells in Patients with di George Syndrome

“…Considering the importance of T regulatory cells and distinct role of their subsets substantial effort was made to detect and analyze thymus derived and peripheral Tregs. Several potential discriminating markers were identified, among them Helios was most thoroughly investigated [4].…”

“…nTregs are thymus derived regulatory cells with a proposed role in central tolerance, while iTregs are induced in the periphery [3]. As the field of Tregs is still evolving, there are some subtle differences in nomenclature, for example Tregs derived in periphery are also named pTregs (for review see [4]). So far there are no reliable markers how to distinguish these subpopulations of Treg cells.…”

1α,25‐dihydroxyvitamin D3 acts via transforming growth factor‐β to up‐regulate expression of immunosuppressive CD73 on human CD4+ Foxp3– T cells

“…A major limitation in the study of regulatory T cells is a lack of specific cell surface markers, particularly in humans . Foxp3 is a widely accepted marker of many regulatory T‐cell populations, but is intracellular so cells must be permeabilized in order to perform staining, which limits the isolation of pure and live cells.…”