Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development.
Marc A. Gavin,Troy R. Torgerson,Evan G. Houston,Paul deRoos,William Y. Ho,Asbjørg Stray-Pedersen,Elizabeth L. Ocheltree,Philip D. Greenberg,Hans D. Ochs,Alexander Y. Rudensky +9 more
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TLDR
Forkhead winged-helix transcription factor Foxp3 serves as the dedicated mediator of the genetic program governing CD25+CD4+ regulatory T cell (T(R)) development and function in mice and the relationship between FOXP3 expression and human T(R) development is addressed.Abstract:
Forkhead winged-helix transcription factor Foxp3 serves as the dedicated mediator of the genetic program governing CD25+CD4+ regulatory T cell (Tr) development and function in mice. In humans, its role in mediating Tr development has been controversial. Furthermore, the fate of Tr precursors in FOXP3 deficiency has yet to be described. Making use of flow cytometric detection of human FOXP3, we have addressed the relationship between FOXP3 expression and human Tr development. Unlike murine Foxp3− T cells, a small subset of human CD4+ and CD8+ T cells transiently up-regulated FOXP3 upon in vitro stimulation. Induced FOXP3, however, did not alter cell-surface phenotype or suppress T helper 1 cytokine expression. Furthermore, only ex vivo FOXP3+ Tr cells persisted after prolonged culture, suggesting that induced FOXP3 did not activate a Tr developmental program in a significant number of cells. FOXP3 flow cytometry was also used to further characterize several patients exhibiting symptoms of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) with or without FOXP3 mutations. Most patients lacked FOXP3-expressing cells, further solidifying the association between FOXP3 deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Interestingly, one patient bearing a FOXP3 mutation enabling expression of stable FOXP3mut protein exhibited FOXP3mut-expressing cells among a subset of highly activated CD4+ T cells. This observation raises the possibility that the severe autoimmunity in FOXP3 deficiency can be attributed, in part, to aggressive T helper cells that have developed from Tr precursors.read more
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Regulatory T Cells and Immune Tolerance
TL;DR: The cellular and molecular basis of Treg development and function is revealed and dysregulation of T Regs in immunological disease is implicates.
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How regulatory T cells work.
TL;DR: The hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate TReg-cell function is proposed.
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A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism
Janine L. Coombes,Karima R.R. Siddiqui,Carolina V. Arancibia-Cárcamo,Jason A. Hall,Cheng-Ming Sun,Yasmine Belkaid,Fiona Powrie +6 more
TL;DR: It is shown that after antigen activation in the intestine, naive T cells acquire expression of Foxp3, and RA is identified as a cofactor in T reg cell generation, providing a mechanism via which functionally specialized gut-associated lymphoid tissue DCs can extend the repertoire of T reg cells focused on the intestine.
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Regulatory T Cells: Mechanisms of Differentiation and Function
TL;DR: Cellular and molecular mechanisms in the differentiation and function of regulatory T cells and their role in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation are discussed.
Journal ArticleDOI
FOXP3 + regulatory T cells in the human immune system
Shimon Sakaguchi,Makoto Miyara,Makoto Miyara,Cristina M. Costantino,Cristina M. Costantino,David A. Hafler,David A. Hafler +6 more
TL;DR: Recent findings regarding human TReg cells are discussed, including the ontogeny and development of TReg cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by TRegcell subsets and factors that regulateTReg cell lineage commitment.
References
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Journal ArticleDOI
Control of Regulatory T Cell Development by the Transcription Factor Foxp3
TL;DR: Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells and retroviral gene transfer of Foxp3 converts naïve T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+.
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Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells
TL;DR: It is reported that the forkhead transcription factor Foxp3 is specifically expressed in CD4+CD25+ regulatory T cells and is required for their development and function and ectopic expression ofFoxp3 confers suppressor function on peripheral CD4-CD25− T cells.
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The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.
Craig L. Bennett,Jacinda R. Christie,Fred Ramsdell,Mary E. Brunkow,Polly J. Ferguson,Luke Whitesell,Thaddeus E. Kelly,Frank T. Saulsbury,Phillip F. Chance,Hans D. Ochs +9 more
TL;DR: Genetic evidence is presented that different mutations of the human gene FOXP3, the ortholog of the gene mutated in scurfy mice (Foxp3), causes IPEX syndrome.
Journal ArticleDOI
An essential role for Scurfin in CD4+CD25+ T regulatory cells.
TL;DR: It is shown that Foxp3 is highly expressed by TR cells and is associated with TR cell activity and phenotype, indicating that the Scurfin and CTLA-4 pathways may intersect and providing further insight into the TR cell lineage.
Journal ArticleDOI
Regulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3
Jason D. Fontenot,Jeffrey P. Rasmussen,Luke M. Williams,James Dooley,Andrew G. Farr,Alexander Y. Rudensky +5 more
TL;DR: Analysis of Foxp3 expression during thymic development suggests that this mechanism is not hard-wired but is dependent on TCR/MHC ligand interactions, and it is shown that expression ofFoxp3 is highly restricted to the subset alphabeta of T cells and, irrespective of CD25 expression, correlates with suppressor activity.