Signals and pathways controlling regulatory T cells

Abstract

Induction of specific immune tolerance to grafts remains the sought-after standard following transplantation. Defined by expression of the Foxp3 (forkhead box protein 3) transcription factor, the regulatory T-cell (Treg) lineage has been noted to exert potent immunoregulatory functions that contribute to specific graft tolerance. In this review, we discuss the known signals and pathways which govern Treg development, both in the thymus and in peripheral sites, as well as lineage maintenance and homeostasis. In particular, we highlight the roles of T-cell receptor signaling, CD28 costimulation, and signals through phosphatidyl inositol 3-kinase (PI3K) and related metabolic pathways in multiple aspects of Treg biology.

The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function

“…Regarding T reg cells, support for the concept of agonist selection has been extensively reviewed elsewhere 4344 , but the seminal observations are: 1) co-expression of an agonist ligand in TCR transgenic mice promotes T reg cell development 45 , at least in some models, 2) FoxP3+ T reg cells have an overlapping repertoire with autoreactive T cells derived from FoxP3-deficient mice 46 , and 3) T reg cells show signs of stronger and/or more recent activation in both the thymus and periphery of TCR signal reporter mice 47 . These data have led to the frequent discussion of a model where T reg cell selection is supported optimally by TCR affinities for self-p/MHCII that are intermediate between positive selection and clonal deletion.…”

The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease

“…On the basis of this model, we posit that vimentin is a crucial upstream molecule involved in limiting Treg activity during immune responses. While Tregs require TCR/ CD28 signaling for their function (55,56), mTORC2/AKT signaling induces TCR/CD28 signaling, which is in turn dampened by PD-1 and CLTA-4, two molecules critical for optimal Treg potency (57,58). Since disruption of vimentin augmented Treg suppression and reduced mTORC2 signaling, this suggests that the vimentin network, and the pathways it supports, may oppose signaling that promotes Treg function, such as the PD-1 and CTLA-4 pathways, via mTORC2 effects.…”

CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity

“…T cell costimulation is important in APC-T cell communication, and these signals are often critical nodes in the regulation of both T reg and effector/ memory T conv activity and homeostasis [18,44,45]. Because the presence or absence of appropriate costimulatory signals likely influences the magnitude of adipose tissue inflammation in obesity, many recent studies have examined the role of costimulatory molecules in this process with somewhat mixed results.…”