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Article ; Online: Development and function of FOXP3+ regulators of immune responses.

Golzari-Sorkheh, Mahdieh / Zúñiga-Pflücker, Juan Carlos

2023 Volume 213, Issue 1, Page(s) 13–22

Abstract: The Forkhead Box P3 (FOXP3) protein is an essential transcription factor for the development and function of regulatory T cells (Tregs), involved in the maintenance of immunological tolerance. Although extensive research over the last decade has ... ...

Abstract	The Forkhead Box P3 (FOXP3) protein is an essential transcription factor for the development and function of regulatory T cells (Tregs), involved in the maintenance of immunological tolerance. Although extensive research over the last decade has investigated the critical role of FOXP3+ cells in preserving immune homeostasis, our understanding of their specific functions remains limited. Therefore, unveiling the molecular mechanisms underpinning the up- and downstream transcriptional regulation of and by FOXP3 is crucial for developing Treg-targeted therapeutics. Dysfunctions in FOXP3+ Tregs have also been found to be inherent drivers of autoimmune disorders and have been shown to exhibit multifaceted functions in the context of cancer. Recent research suggests that these cells may also be involved in tissue-specific repair and regeneration. Herein, we summarize current understanding of the thymic-transcriptional regulatory landscape of FOXP3+ Tregs, their epigenetic modulators, and associated signaling pathways. Finally, we highlight the contributions of FOXP3 on the functional development of Tregs and reflect on the clinical implications in the context of pathological and physiological immune responses.
MeSH term(s)	Humans ; T-Lymphocytes, Regulatory ; Autoimmune Diseases/metabolism ; Immune Tolerance ; Immunity ; Forkhead Transcription Factors
Chemical Substances	Forkhead Transcription Factors ; FOXP3 protein, human
Language	English
Publishing date	2023-04-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218531-3
ISSN	1365-2249 ; 0009-9104 ; 0964-2536
ISSN (online)	1365-2249
ISSN	0009-9104 ; 0964-2536
DOI	10.1093/cei/uxad048
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Article ; Online: Thymus aging and immune reconstitution, progresses and challenges.

Li, Yue Ru / Zúñiga-Pflücker, Juan Carlos

Seminars in immunology

2023 Volume 70, Page(s) 101837

Abstract: Thymus is a primary lymphoid organ essential for the development of T lymphocytes. Age-related thymic involution is a prominent feature of immune senescence. The thymus undergoes rapid growth during fetal and neonatal development, peaks in size before ... ...

Abstract	Thymus is a primary lymphoid organ essential for the development of T lymphocytes. Age-related thymic involution is a prominent feature of immune senescence. The thymus undergoes rapid growth during fetal and neonatal development, peaks in size before puberty and then begins to undergo a decrease in cellularity with age. Dramatic changes occur with age-associated thymic involution. The most prominent features of thymic involution include: (i) epithelial structure disruption, (ii) adipogenesis, and (iii) thymocyte development arrest. There is a sex disparity in thymus aging. It is a multifactorial process controlled and regulated by a series of molecules, including the transcription factor FOXN1, fibroblast and keratinocyte growth factors (FGF and KGF, respectively), sex steroids, Notch signaling, WNT signaling, and microRNAs. Nevertheless, there is still no satisfactory evolutionary or physiological explanation for age-associated thymic involution, and understanding the precise mechanism(s) for thymus aging remains challenging. Sustained thymic regeneration has yet to be achieved by sex steroid ablation. Recent preclinical studies indicate that long-term thymic reconstitution can be achieved via adoptive transfer of in vitro-generated progenitor T (proT) cells, and improvements in the methods for the generation of human proT cells make this an attractive approach. Future clinical applications may rely on new applications integrating proT cells, cytokine support and sex-steroid inhibition treatments.
MeSH term(s)	Infant, Newborn ; Humans ; Immune Reconstitution ; Aging ; Thymus Gland/physiology ; T-Lymphocytes ; Gonadal Steroid Hormones ; Steroids
Chemical Substances	Gonadal Steroid Hormones ; Steroids
Language	English
Publishing date	2023-08-31
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2023.101837
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Article ; Online: Thymic Microenvironment: Interactions Between Innate Immune Cells and Developing Thymocytes.

Wang, Helen / Zúñiga-Pflücker, Juan Carlos

Frontiers in immunology

2022 Volume 13, Page(s) 885280

Abstract: The thymus is a crucial organ for the development of T cells. T cell progenitors first migrate from the bone marrow into the thymus. During the journey to become a mature T cell, progenitors require interactions with many different cell types within the ... ...

Abstract	The thymus is a crucial organ for the development of T cells. T cell progenitors first migrate from the bone marrow into the thymus. During the journey to become a mature T cell, progenitors require interactions with many different cell types within the thymic microenvironment, such as stromal cells, which include epithelial, mesenchymal and other non-T-lineage immune cells. There are two crucial decision steps that are required for generating mature T cells: positive and negative selection. Each of these two processes needs to be performed efficiently to produce functional MHC-restricted T cells, while simultaneously restricting the production of auto-reactive T cells. In each step, there are various cell types that are required for the process to be carried out suitably, such as scavengers to clean up apoptotic thymocytes that fail positive or negative selection, and antigen presenting cells to display self-antigens during positive and negative selection. In this review, we will focus on thymic non-T-lineage immune cells, particularly dendritic cells and macrophages, and the role they play in positive and negative selection. We will also examine recent advances in the understanding of their participation in thymus homeostasis and T cell development. This review will provide a perspective on how the thymic microenvironment contributes to thymocyte differentiation and T cell maturation.
MeSH term(s)	Antigen-Presenting Cells ; Cell Differentiation ; Immunity, Innate ; Lymphocyte Activation ; Thymocytes
Language	English
Publishing date	2022-04-08
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.885280
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Article ; Online: Induction of Human T Cell Development In Vitro with OP9-DL4-7FS Cells Expressing Human Cytokines.

Mohtashami, Mahmood / Brauer, Patrick M / Zúñiga-Pflücker, Juan Carlos

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2580, Page(s) 249–260

Abstract: For nearly a generation now, OP9-DL1 and OP9-DL4 cells have provided an efficient and reliable cell system to generate T cells from mouse and human hematopoietic stem cells (HSCs) and pluripotent stem cells. OP9-DL1 and OP9-DL4 were originally derived ... ...

Abstract	For nearly a generation now, OP9-DL1 and OP9-DL4 cells have provided an efficient and reliable cell system to generate T cells from mouse and human hematopoietic stem cells (HSCs) and pluripotent stem cells. OP9-DL1 and OP9-DL4 were originally derived from the OP9 mouse bone marrow stromal cell line, which was transduced to ectopically express Delta-like 1 or 4 proteins, respectively. OP9-DL cells mimic the thymic microenvironment in that when cocultured with mouse or human (h) HSCs, they interact with and activate Notch receptors present on HSCs, required for T cell differentiation. The HSC/OP9-DL cocultures require additional cytokines that are necessary for survival and proliferation of hematopoietic cells. For hHSCs, these factors are interleukin-7 (IL-7), stem cell factor (SCF), and FMS-like tyrosine kinase 3 ligand (FLT3L) that are normally exogenously added to the cocultures. In this chapter, we describe methods for establishing a novel and improved version of OP9-DL4 cells, called OP9-DL4-7FS cells that circumvent the addition of these costly cytokines, by transducing OP9-DL4 cell line to express human IL-7, FLT3L, and SCF (7FS). Herein, we describe the protocol for the generation of OP9-DL4-7FS cells and the conditions for OP9-DL4-7FS/hHSC coculture to support T cell lineage initiation and expansion while comparing it to the now "classic" OP9-DL4 coculture. The use of OP9-DL4-7FS cell system will provide an improved and cost-effective method to the commonly used OP9-DL/HSC coculture for studying both mouse and human T cell development.
MeSH term(s)	Humans ; Mice ; Animals ; Interleukin-7/metabolism ; Cytokines/metabolism ; Cell Differentiation ; Hematopoietic Stem Cells ; Coculture Techniques ; T-Lymphocytes ; Stromal Cells/metabolism
Chemical Substances	Interleukin-7 ; Cytokines
Language	English
Publishing date	2022-11-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2740-2_15
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: High-Oxygen Submersion Fetal Thymus Organ Cultures Enable FOXN1-Dependent and -Independent Support of T Lymphopoiesis.

Han, Jianxun / Zúñiga-Pflücker, Juan Carlos

Frontiers in immunology

2021 Volume 12, Page(s) 652665

Abstract: T cell development is effectively supported in fetal thymus organ cultures (FTOCs), which places thymus lobes atop an air-liquid interface (ALI) culture system. The direct exposure to air is critical for its success, as fetal thymus lobes placed in low ... ...

Abstract	T cell development is effectively supported in fetal thymus organ cultures (FTOCs), which places thymus lobes atop an air-liquid interface (ALI) culture system. The direct exposure to air is critical for its success, as fetal thymus lobes placed in low oxygen submersion (LOS)-FTOCs fail to support thymocyte development. However, submersion cultures performed in the presence of high concentration of ambient oxygen (60~80%) allow for normal thymocyte development, but the underlying mechanism for this rescue has remained elusive. Here, we show that FOXN1 expression in thymic epithelial cells (TECs) from LOS-FTOCs was greatly reduced compared to conventional ALI-FTOCs. Consequently, the expression of important FOXN1 target genes, including
MeSH term(s)	Animals ; Biomarkers ; Cell Differentiation ; Forkhead Transcription Factors/metabolism ; Immunophenotyping ; Lymphopoiesis ; Mice ; Organ Culture Techniques ; Oxygen/metabolism ; T-Lymphocyte Subsets/cytology ; T-Lymphocyte Subsets/metabolism ; Thymocytes/cytology ; Thymocytes/metabolism ; Thymus Gland/cytology ; Thymus Gland/metabolism
Chemical Substances	Biomarkers ; Forkhead Transcription Factors ; Whn protein ; Oxygen (S88TT14065)
Language	English
Publishing date	2021-03-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.652665
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Article ; Online: A 2020 View of Thymus Stromal Cells in T Cell Development.

Han, Jianxun / Zúñiga-Pflücker, Juan Carlos

Journal of immunology (Baltimore, Md. : 1950)

2021 Volume 206, Issue 2, Page(s) 249–256

Abstract: The thymus is an intricate primary lymphoid organ, wherein bone marrow-derived lymphoid progenitor cells are induced to develop into functionally competent T cells that express a diverse TCR repertoire, which is selected to allow for the recognition of ... ...

Abstract	The thymus is an intricate primary lymphoid organ, wherein bone marrow-derived lymphoid progenitor cells are induced to develop into functionally competent T cells that express a diverse TCR repertoire, which is selected to allow for the recognition of foreign Ags while avoiding self-reactivity or autoimmunity. Thymus stromal cells, which can include all non-T lineage cells, such as thymic epithelial cells, endothelial cells, mesenchymal/fibroblast cells, dendritic cells, and B cells, provide signals that are essential for thymocyte development as well as for the homeostasis of the thymic stroma itself. In this brief review, we focus on the key roles played by thymic stromal cells during early stages of T cell development, such as promoting the homing of thymic-seeding progenitors, inducing T lineage differentiation, and supporting thymocyte survival and proliferation. We also discuss recent advances on the transcriptional regulation that govern thymic epithelial cell function as well as the cellular and molecular changes that are associated with thymic involution and regeneration.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Lineage ; Humans ; Lymphocyte Activation ; Stromal Cells/immunology ; T-Lymphocytes/immunology ; Thymus Gland/cytology
Language	English
Publishing date	2021-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2000889
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Ud II Zs.37: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Editorial: Molecular switches of the immune system: The E-protein/Id axis in hematopoietic development and function.

Sigvardsson, Mikael / Kee, Barbara L / Zúñiga-Pflücker, Juan Carlos / Anderson, Michele K

Frontiers in immunology

2022 Volume 13, Page(s) 1062734

MeSH term(s)	Hematopoiesis ; Transcription Factors ; Immune System
Chemical Substances	Transcription Factors
Language	English
Publishing date	2022-11-04
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.1062734
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Article ; Online: Thymus Reconstitution in Young and Aged Mice Is Facilitated by

Mohtashami, Mahmood / Li, Yue Ru / Lee, Christina R / Zúñiga-Pflücker, Juan Carlos

Frontiers in immunology

2022 Volume 13, Page(s) 926773

Abstract: The prolonged lag in T cell recovery seen in older patients undergoing hematopoietic stem cell transplant (HSCT), after chemo-/radiotherapy, can lead to immune dysfunction. As a result, recovering patients may experience a relapse in malignancies and ... ...

Abstract	The prolonged lag in T cell recovery seen in older patients undergoing hematopoietic stem cell transplant (HSCT), after chemo-/radiotherapy, can lead to immune dysfunction. As a result, recovering patients may experience a relapse in malignancies and opportunistic infections, leading to high mortality rates. The delay in T cell recovery is partly due to thymic involution, a natural collapse in the size and function of the thymus, as individuals age, and partly due to the damage sustained by the thymic stromal cells through exposure to chemo-/radiotherapy. There is a clear need for new strategies to accelerate intrathymic T cell reconstitution when treating aged patients to counter the effects of involution and cancer therapy regimens. Adoptive transfer of human progenitor T (proT) cells has been shown to accelerate T cell regeneration in radiation-treated young mice and to restore thymic architecture in immunodeficient mice. Here, we demonstrate that the adoptive transfer of
MeSH term(s)	Aged ; Animals ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Mice ; Opportunistic Infections/etiology
Language	English
Publishing date	2022-07-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.926773
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Article ; Online: T cell development runs marrow deep.

Zúñiga-Pflücker, Juan Carlos

The Journal of experimental medicine

2015 Volume 212, Issue 5, Page(s) 599–600

MeSH term(s)	Animals ; Bone Marrow Cells/immunology ; Intracellular Signaling Peptides and Proteins/immunology ; Membrane Proteins/immunology ; Mesenchymal Stem Cells/immunology ; T-Lymphocytes/immunology ; Thymus Gland/immunology
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Membrane Proteins
Language	English
Publishing date	2015-05-04
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.2125insight3
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Article ; Online: Close Quarters Can Be a Good Fit for Stem Cells to Become T Cells.

Trotman-Grant, Ashton / Zúñiga-Pflücker, Juan Carlos

Cell stem cell

2019 Volume 24, Issue 3, Page(s) 345–347

Abstract: Human pluripotent stem cells (PSCs) could potentially provide a potentially unlimited supply of T cells. In this issue of Cell Stem Cell, Montel-Hagen et al. (2019) take advantage of a three-dimensional mouse stromal cell-based system that combines ... ...

Abstract	Human pluripotent stem cells (PSCs) could potentially provide a potentially unlimited supply of T cells. In this issue of Cell Stem Cell, Montel-Hagen et al. (2019) take advantage of a three-dimensional mouse stromal cell-based system that combines mesoderm specification with organoid-induced hematopoietic differentiation to enable commitment, selection, and maturation of conventional human T cells.
MeSH term(s)	Animals ; Cell Differentiation ; Hematopoiesis ; Humans ; Mice ; Organoids ; Pluripotent Stem Cells ; T-Lymphocytes
Language	English
Publishing date	2019-03-05
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2019.02.013
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Zs.MG 75: Show issues

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