Induction, control, and plasticity of Treg cells: The immune regulatory network revised?

Abstract

The revival of the old and, for several years, abandoned era of suppressor T cells came in the 1990s with two works that resurrected the idea of CD8 + suppressor T cells [1,2]. The revival was further strengthened when a subset of CD4 + T cells constitutively expressing high levels of the IL-2R α-chain (CD25) and possessing suppressor activity was identified [3]. These cells, termed regulatory T (Treg) cells, were able to prevent disease in various models of autoimmunity, and to suppress transplant rejection and tumor immunity (as reviewed in [5,6]). The presence in the thymus of a subset of CD4 + CD25 + thymocytes that displayed suppressor activity indicated that Treg-cell development occurs in this organ (reviewed in [6]). However, the undisputed confirmation of the existence of Treg cells relates to the discovery that the genetic defect causing IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, also known as XLAAD (X-linked autoimmunity-allergic dysregulation syndrome)) in humans or Correspondence: Dr. Vincenzo Barnaba e-mail: vincenzo.barnaba@uniroma1.it the equivalent condition in mice (Scurfy mice) is due to mutations in the gene encoding the Foxp3 transcription factor, which is typically expressed in CD4 + CD25 high Treg cells (reviewed in [5,6]).The fundamental milestones that have supported the correlation between Foxp3 and the Treg-cell lineage are based on discoveries ascertaining that: (i) Foxp3 is absolutely required in Tregcell differentiation in the thymus, as indicated by the analysis of Foxp3-deficient mice and bone-marrow transfer studies; (ii) retroviral transfer of the Foxp3 gene into naïve T cells conferring suppressor activity and a Treg-cell phenotype; (iii) sustained Foxp3 expression in mature Treg cells being necessary to maintain the Treg-cell phenotype and function and preventing the cells trans-differentiating into different types of effector T cells; and (iv) the lack of Treg cells being the cause of fatal autoimmunity arising from Foxp3 deficiency in several experimental models (reviewed in [5,6]). In addition, the finding that some CD4 + T cells with either low CD25 levels or lacking CD25 (i.e., conventional T (Tconv) cells) can also express Foxp3 and display potent suppressor activity (reviewed in [6]) not only supported the key role of Foxp3 in Treg-cell differentiation but also suggested a dichotomy [7][8][9]. It has been proposed that demethylated TSDR is accessible to various transcription factors (CREB, activating transcription factor, etc.), and that it can hence act as an enhancer of the Foxp3 promoter, ultimately increasing the Foxp3 stabilization [7][8][9]. By contrast, TSDR is partially methylated in iTreg cells and this is associated with unstable Foxp3 expression and with the potentiality to convert into different effector T cell types, a process referred to as plasticity [7][8][9][10]. Indeed, under particular conditions in vitro (i.e., by using azacytidine inhibiting DNA methylation), iTreg cells can ultimately differentiate into fully ...

Divergent effects of type-I interferons on regulatory T cells

“…IFN promoted Th1 polarization at the expense of peripheral Treg induction, a data indicating that, during inflammation, IFN may subvert microenvironmental networks normally promoting tolerance maintenance, as in the gut. In addition, the finding that type-I IFNs are also potent inducers of PD-L1 on a variety of cells including Treg is consistent with the evidence showing that the PD-1 is overexpressed by activated Treg and, upon PD-L1 interaction, negatively regulates the expansion and suppressive function of activated Treg by controlling STAT-5 phosphorylation, at the site of inflammation in chronic HCV infection [15,26]. Such a mechanism (contra-suppression?)…”

Relevance of Foxp3+ regulatory T cells for early and late phases of murine sepsis

“…Natural Treg cells are completely demethylated within the foxp3‐TSDR , whereas murine induced Treg cells may either exhibit a methylated foxp3‐TSDR or differentiate into fully stable Treg cells with a demethylated foxp3‐TSDR under particular conditions, e.g. by antigen‐specific signals through tolerogenic DEC205 vaccination . Hence, this methylation is a valid marker characterizing stable committed Treg cells regardless of the Treg cell type (natural or induced) …”

Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue

“…PD‐1, considered as an inhibitory receptor delivering negative signals to conventional T cells (Tconvs), sustains development, maintenance, and suppressive function of peripherally induced Tregs upon engagement with its own ligand (PD‐L1) . On the other side, PD‐1 tempers expansion and function of already established Tregs . Contrary to PD‐1, OX40 is considered as a costimulatory molecule conveying prosurvival signals to Tconvs .…”