Journal ArticleDOI
Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis.
Takashi Sekiya,Ikkou Kashiwagi,Rei Yoshida,Tomohiro Fukaya,Rimpei Morita,Akihiro Kimura,Hiroshi Ichinose,Daniel Metzger,Pierre Chambon,Akihiko Yoshimura +9 more
TLDR
The results suggest that Nr4a receptors have key roles in determining CD4+ T cell fates in the thymus and thus contribute to immune homeostasis.Abstract:
Regulatory T cells (T(reg) cells) develop from progenitor thymocytes after the engagement of T cell antigen receptors (TCRs) with high-affinity ligands, but the underlying molecular mechanisms are still unclear. Here we show that the Nr4a nuclear receptors, which are encoded by immediate-early genes upregulated by TCR stimulation in thymocytes, have essential roles in T(reg) cell development. Mice that lacked all Nr4a factors could not produce T(reg) cells and died early owing to systemic autoimmunity. Nr4a receptors directly activated the promoter of the gene encoding the transcription factor Foxp3, and forced activation of Nr4a receptors bypassed low-strength TCR signaling to drive the T(reg) cell developmental program. Our results suggest that Nr4a receptors have key roles in determining CD4(+) T cell fates in the thymus and thus contribute to immune homeostasis.read more
Citations
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Journal ArticleDOI
Development and Maintenance of Regulatory T cells
TL;DR: Understanding how epigenetic alterations and Foxp3 expression coordinately control Treg-cell-specific gene regulation will enable better control of immune responses by targeting the generation and maintenance of Treg cells.
Journal ArticleDOI
NR4A transcription factors limit CAR T cell function in solid tumours.
Joyce Chen,Isaac F. López-Moyado,Isaac F. López-Moyado,Hyungseok Seo,Chan-Wang J. Lio,Laura J. Hempleman,Takashi Sekiya,Akihiko Yoshimura,James P. Scott-Browne,Anjana Rao +9 more
TL;DR: Transfer of NR4A-deficient T cells expressing chimeric antigen receptors is shown to reduce tumour burden and increase survival by shifting T cell transcriptional programs away from exhaustion and towards increased effector function.
Journal ArticleDOI
TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion
Hyungseok Seo,Joyce Chen,Joyce Chen,Edahí González-Avalos,Edahí González-Avalos,Daniela Samaniego-Castruita,Daniela Samaniego-Castruita,Arundhoti Das,Yueqiang H. Wang,Isaac F. López-Moyado,Isaac F. López-Moyado,Romain O. Georges,Wade Zhang,Wade Zhang,Atsushi Onodera,Atsushi Onodera,Cheng-Jang Wu,Li-Fan Lu,Patrick G. Hogan,Patrick G. Hogan,Avinash Bhandoola,Anjana Rao +21 more
TL;DR: The high-mobility group (HMG)-box transcription factors TOX and TOX2, as well as members of the NR4A family of nuclear receptors, are targets of the calcium/calcineurin-regulated transcription factor NFAT, even in the absence of its partner AP-1 (FOS-JUN).
Journal ArticleDOI
Regulatory circuits of T cell function in cancer
TL;DR: T cell-intrinsic molecular alterations and metabolic communication in the tumour microenvironment are discussed and identification of the underlying molecular drivers of T cell dysfunction is essential for the continued progress of cancer research and therapy.
Journal ArticleDOI
T cell receptor signalling in the control of regulatory T cell differentiation and function
Ming O. Li,Alexander Y. Rudensky +1 more
TL;DR: The emerging understanding of TCR-guided differentiation of TReg cells in the context of their function in health and disease is discussed.
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+.
Journal ArticleDOI
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.
Journal ArticleDOI
Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3
Wanjun Chen,Wenwen Jin,Neil J. Hardegen,Ke Jian Lei,Li Li,Nancy J. Marinos,George McGrady,Sharon M. Wahl +7 more
TL;DR: Novel evidence is presented that conversion of naive peripheral CD4+CD25− T cells into anergic/suppressor cells that are CD25+, CD45RB−/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor β (TGF-β).
Journal ArticleDOI
Naturally Arising CD4+ Regulatory T Cells for Immunologic Self-Tolerance and Negative Control of Immune Responses
TL;DR: How naturally arising CD25+CD4+ regulatory T cells contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses, and how they can be exploited to prevent and treat autoimmune disease, allergy, cancer, and chronic infection, or establish donor-specific transplantation tolerance are discussed.
Journal ArticleDOI
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.
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Naganari Ohkura,Naganari Ohkura,Masahide Hamaguchi,Masahide Hamaguchi,Hiromasa Morikawa,Hiromasa Morikawa,Kyoko Sugimura,Tanaka Atsushi,Yoshinaga Ito,Motonao Osaki,Motonao Osaki,Yoshiaki Tanaka,Riu Yamashita,Naoko Nakano,Jochen Huehn,Hans Joerg Fehling,Tim Sparwasser,Kenta Nakai,Shimon Sakaguchi,Shimon Sakaguchi +19 more