Two Functional Subsets of FOXP3+ Regulatory T Cells in Human Thymus and Periphery

Abstract

Previous studies suggest that thymus produces a homogenous population of natural regulatory T (Treg) cells that express a transcriptional factor FOXP3 and control autoimmunity through a cell-contact-dependent mechanism. We found two subsets of FOXP3+ natural Treg cells defined by the expression of the costimulatory molecule ICOS in the human thymus and periphery. Whereas the ICOS+FOXP3+ Treg cells used interleukin-10 to suppress dendritic cell function and transforming growth factor (TGF)-beta to suppress T cell function, the ICOS-FOXP3+ Treg cells used TGF-beta only. The survival and proliferation of the two subsets of Treg cells were differentially regulated by signaling through ICOS or CD28, respectively. We suggest that the selection of natural Treg cells in thymus is coupled with Treg cell differentiation into two subsets imprinted with different cytokine expression potentials and use both cell-contact-dependent and independent mechanisms for immunosuppression in periphery.

Single nucleotide polymorphisms in the promoter regions of Foxp3 and ICOSLG genes are associated with Alopecia Areata

“…Upon activation, Treg also express the inducible costimulator (ICOS) [21], a receptor that modulates their function [22]. ICOS binds to a unique ligand, ICOS ligand (ICOSLG) [23,24].…”

LAG-3 Expression Defines a Subset of CD4+CD25highFoxp3+ Regulatory T Cells That Are Expanded at Tumor Sites

“…However, it has been shown that the expression of MHC-II and ICOS characterizes natural Treg cells that are functionally different (13,14). These latest data suggest that Treg cells can be further differentiated into discrete subsets that differently rely on cell-to-cell contact and on IL-10 or TGF-b production for their functional activities.…”

“…Further phenotypic studies revealed that other subclasses of human natural Treg cells could be identified based on the expression of molecules, such as MHC-II, CD45RO/RA, CCR7, and costimulatory molecules, such as ICOS (11)(12)(13)(14). The expression of CD45RO/ RA and CCR7 identifies populations that are at different in vivo differentiation stages, whereas their combined expression defines the presence of the natural naive, effector memory, or central memory Treg cells.…”

Budesonide increases TLR4 and TLR2 expression in Treg lymphocytes of allergic asthmatics

“…T regulatory activities are mainly related to naturally occurring CD4þ/CD25þ Tregs and to CD4þ/CD25À inducible Tregs [27]. It has been previously demonstrated that BUD increases costimulatory activities in CD4þ/CD25þ further supporting the concept that this drug is effective in controlling T lymphocyte activation also improving the function and the activities of the Tregs.…”

“…Tregs control effector immune responses through a diverse array of mechanisms including secretion of the antiinflammatory cytokines TGF and IL-10 [32]. IL-10 is essential not only for suppression of effector cells by Treg cells but also for their differentiation [27]. IL-10, produced by a number of different cells, affecting antigen presenting cell function, dendritic cell maturation as well as the activation of co-stimulatory molecules, can inhibit both Th1 and Th2 type responses [14].…”