FOXP3+ regulatory T cells in the human immune system (original) (raw)
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The Foxp3+ regulatory T cell: a jack of all trades, master of regulation
Nature Immunology, 2008
The function of regulatory T cells (T reg cells) has been attributed to a growing number of diverse pathways, molecules and processes. Seemingly contradictory conclusions regarding the mechanisms underlying T reg cell suppressive activity have revitalized skeptics in the field who challenge the core validity of the idea of T reg cells as central immune regulators. However, we note that a consensus may be emerging from the data: that multiple T reg cell functions act either directly or indirectly at the site of antigen presentation to create a regulatory milieu that promotes bystander suppression and infectious tolerance. Thus, the versatility and adaptability of the Foxp3 + T reg cells may in fact be the best argument that these cells are 'multitalented masters of immune regulation'.
Proceedings of The National Academy of Sciences, 2009
Natural regulatory T cells (Treg) represent a distinct lineage of T lymphocytes committed to suppressive functions, and expression of the transcription factor Foxp3 is thought to identify this lineage specifically. Here we report that, whereas the majority of natural CD4 ؉ Foxp3 ؉ T cells maintain stable Foxp3 expression after adoptive transfer to lymphopenic or lymphoreplete recipients, a minor fraction enriched within the CD25 ؊ subset actually lose it. Some of those Foxp3 ؊ T cells adopt effector helper T cell (Th) functions, whereas some retain ''memory'' of previous Foxp3 expression, reacquiring Foxp3 upon activation. This minority ''unstable'' population exhibits flexible responses to cytokine signals, relying on transforming growth factor- to maintain Foxp3 expression and responding to other cytokines by differentiating into effector T h in vitro. In contrast, CD4 ؉ Foxp3 ؉ CD25 high T cells are resistant to such conversion to effector Th even after many rounds of cell division. These results demonstrate that natural Foxp3 ؉ T cells are a heterogeneous population consisting of a committed Treg lineage and an uncommitted subpopulation with developmental plasticity.
The Journal of Immunology, 2009
Homeostasis in the immune system is maintained by specialized regulatory CD4 ؉ T cells (T reg) expressing transcription factor Foxp3. According to the current paradigm, high-affinity interactions between TCRs and class II MHC-peptide complexes in thymus "instruct" developing thymocytes to up-regulate Foxp3 and become T reg cells. However, the loss or down-regulation of Foxp3 does not disrupt the development of T reg cells but abrogates their suppressor function. In this study, we show that Foxp3-deficient T reg cells in scurfy mice harboring a null mutation of the Foxp3 gene retained cellular features of T reg cells including in vitro anergy, impaired production of inflammatory cytokines, and dependence on exogenous IL-2 for proliferation and homeostatic expansion. Foxp3-deficient T reg cells expressed a low level of activation markers, did not expand relative to other CD4 ؉ T cells, and produced IL-4 and immunomodulatory cytokines IL-10 and TGF- when stimulated. Global gene expression profiling revealed significant similarities between T reg cells expressing and lacking Foxp3. These results argue that Foxp3 deficiency alone does not convert T reg cells into conventional effector CD4 ؉ T cells but rather these cells constitute a distinct cell subset with unique features.
Regulatory T Cells: Regulation of Identity and Function
Frontiers in Immunology, 2021
T regulatory cells suppress a variety of immune responses to self-antigens and play a role in peripheral tolerance maintenance by limiting autoimmune disorders, and other pathological immune responses such as limiting immune reactivity to oncoprotein encoded antigens. Forkhead box P3 (FOXP3) expression is required for Treg stability and affects functional activity. Mutations in the master regulator FOXP3 and related components have been linked to autoimmune diseases in humans, such as IPEX, and a scurfy-like phenotype in mice. Several lines of evidence indicate that Treg use a variety of immunosuppressive mechanisms to limit an immune response by targeting effector cells, including secretion of immunoregulatory cytokines, granzyme/perforin-mediated cell cytolysis, metabolic perturbation, directing the maturation and function of antigen-presenting cells (APC) and secretion of extracellular vesicles for the development of immunological tolerance. In this review, several regulatory mec...
Immunity, 2012
The emerging notion of environment-induced reprogramming of Foxp3 + regulatory T (Treg) cells into helper T (Th) cells remains controversial. By genetic fate mapping or adoptive transfers, we have identified a minor population of nonregulatory Foxp3 + T cells exhibiting promiscuous and transient Foxp3 expression, which gave rise to Foxp3 À (''exFoxp3'') Th cells and selectively accumulated in inflammatory cytokine milieus or in lymphopenic environments including those in early ontogeny. In contrast, Treg cells did not undergo reprogramming under those conditions irrespective of their thymic or peripheral origins. Moreover, although a few Treg cells transiently lose Foxp3 expression, such ''latent'' Treg cells retained their memory and robustly reexpressed Foxp3 and suppressive function upon activation. This study establishes that Treg cells constitute a stable cell lineage, whose committed state in a changing environment is ensured by DNA demethylation of the Foxp3 locus irrespectively of ongoing Foxp3 expression.
How regulatory T cells work NIH Public Access
Regulatory T (T reg) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting anti-tumour immunity. Given that T reg cells can have both beneficial and deleterious effects, there is considerable interest in determining their mechanisms of action. In this Review, we discuss the basic mechanisms used by T reg cells to mediate suppression, and discuss whether one or many of these mechanisms are likely to be crucial for T reg-cell function. In addition, we present the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate T reg-cell function. Several sophisticated regulatory mechanisms are used to maintain immune homeostasis, prevent autoimmunity and moderate inflammation induced by pathogens and environmental insults. Chief amongst these are regulatory T (T reg) cells that are now widely regarded as the primary mediators of peripheral tolerance. Although T reg cells play a pivotal role in preventing autoimmune diseases, such as type 1 diabetes 1,2 , and limiting chronic inflammatory diseases, such as asthma and inflammatory bowel disease (IBD) 3,4 , they also block beneficial responses by preventing sterilizing immunity to certain pathogens 5,6 and limiting anti-tumour immunity 7. A seminal advance in the analysis of T reg cells came with the identification of a key transcription factor, forkhead box P3 (FOXP3), that is required for their development, maintenance and function 8,9. Mice and patients that lack FOXP3 develop a profound autoimmune-like lymphoproliferative disease that graphically emphasizes the importance of T reg cells in maintaining peripheral tolerance 10-12 (BOX 1). Although FOXP3 has been proposed as the master regulator of T reg cells that controls the expression of multiple genes that mediate their regulatory activity 13,14 , this has been recently challenged raising the possibility that other transcriptional events may operate upstream of and/or concurrently with FOXP3 to mediate T reg-cell development 15. While Foxp3 has proven to be an invaluable marker for murine T reg cells, its role in human T reg cells is less straightforward (see BOX 2 for a discussion of T reg-cell markers). Humans that lack FOXP3 develop immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), a severe autoimmune disease that presents early in infancy. Although FOXP3 appears to be required for human T reg-cell development and function, expression of FOXP3 alone is clearly not sufficient as a significant percentage of human activated T cells express FOXP3 and yet do not possess regulatory activity 16-20. Furthermore, induction of FOXP3 in human T cells by transforming growth factor-β (TGFβ) does not confer a regulatory phenotype, in contrast to their murine counterparts 20. Consequently, FOXP3 is not a good marker for human T reg cells (BOX 2). Whether this distinction is due to intrinsic differences between mouse and human FOXP3 and/or a requirement for an additional cofactor/ transcription factor is an important question that needs to be resolved.