Natural and Adaptive Foxp3+ Regulatory T Cells: More of the Same or a Division of Labor?

Abstract

Adaptive Foxp3(+)CD4(+) regulatory T (iTreg) cells develop outside the thymus under subimmunogenic antigen presentation, during chronic inflammation, and during normal homeostasis of the gut. iTreg cells are essential in mucosal immune tolerance and in the control of severe chronic allergic inflammation, and most likely are one of the main barriers to the eradication of tumors. The Foxp3(+) iTreg cell repertoire is drawn from naive conventional CD4(+) T cells, whereas natural Treg (nTreg) cells are selected by high-avidity interactions in the thymus. The full extent of differences and similarities between iTreg and nTreg cells is yet to be defined. We speculate that iTreg cell development is driven by the need to maintain a noninflammatory environment in the gut, to suppress immune responses to environmental and food allergens, and to decrease chronic inflammation, whereas nTreg cells prevent autoimmunity and raise the activation threshold for all immune responses.

CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity

“…Rag À/À mice crossed to TCR transgenic mice expressing MHCclass-II-restricted TCRs, which recognize nonself peptides, represent a widely used tool to study Foxp3 induction in CD4 1 T cells as those mice are devoid of nTregs [21]. Conversely, we used Rag1 À/À Â OTI mice expressing a MHC-class-I-restricted OVA 257-264 -specific TCR to study Foxp3 induction in CD8 1 T cells, considering low numbers of CD8 1 Foxp3 1 T cells in vivo and limited knowledge of their development.…”

Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

“…The peripheral Treg pool is comprised of naturally arising Tregs (nTregs) that develop in the thymus and inducible Tregs (iTregs) that are converted from conventional CD4 + T cells (Tconvs) in the periphery (1)(2)(3)(4). Tregs constitute 5-15% of the total CD4 + T cell pool in the steady-state (5,6).…”

c‐Rel: A pioneer in directing regulatory T‐cell lineage commitment?

“…In addition, it has also become evident that Foxp3 1 Treg can also be generated from peripheral naive CD4 1 T cells upon ''tolerogenic'' antigen presentation in vivo or activation in the presence of TGF-b in vitro (so-called induced iTreg) [6]. Although thymusderived Treg and peripherally generated Treg share some functional and phenotypic characteristics, it is becoming clear that they are different in many aspects, particularly in terms of gene expression, phenotypic stability and mechanistic requirements for differentiation [5][6][7][8]. Although TCR signals are central for both thymic and peripheral Treg induction, ''quality'' of the TCR signals appears different.…”

“…Although TCR signals are central for both thymic and peripheral Treg induction, ''quality'' of the TCR signals appears different. While thymic Treg differentiation requires high-affinity/avidity TCR interactions together with costimulatory signals through CD28, peripheral Treg induction depends on suboptimal TCR stimulation in the absence of CD28 co-stimulation and on TGF-b [5,6]. Moreover, TGF-b-induced iTreg exhibit unstable Foxp3 expression, while the majority (although not all) of natural Foxp3 1 T cells exhibit stable Foxp3 expression [8,9].…”