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1.
Front Immunol ; 12: 701924, 2021.
Article in English | MEDLINE | ID: mdl-34421907

ABSTRACT

Runx proteins (also known as Runt-domain transcription factors) have been studied for a long time as key regulators of cellular differentiation. RUNX2 has been described as essential for osteogenesis, whereas RUNX1 and RUNX3 are known to control blood cell development during different stages of cell lineage specification. However, recent studies show evidence of complex relationships between RUNX proteins, chromatin-modifying machinery, the cytoskeleton and different transcription factors in various non-embryonic contexts, including mature T cell homeostasis, inflammation and cancer. In this review, we discuss the diversity of Runx functions in mature T helper cells, such as production of cytokines and chemokines by different CD4 T cell populations; apoptosis; and immunologic memory acquisition. We then briefly cover recent findings about the contribution of RUNX1, RUNX2 and RUNX3 to various immunologic diseases. Finally, we discuss areas that require further study to better understand the role that Runx proteins play in inflammation and immunity.


Subject(s)
Core Binding Factor alpha Subunits/immunology , T-Lymphocytes/immunology , Thymus Gland/immunology , Animals , Humans , Immunity/immunology , Immunologic Memory/immunology , Inflammation/immunology
2.
J Allergy Clin Immunol ; 147(5): 1549-1560, 2021 05.
Article in English | MEDLINE | ID: mdl-33965092

ABSTRACT

Innate lymphoid cells (ILCs) mainly reside at barrier surfaces and regulate tissue homeostasis and immunity. ILCs are divided into 3 groups, group 1 ILCs, group 2 ILCs, and group 3 ILC3, on the basis of their similar effector programs to T cells. The development of ILCs from lymphoid progenitors in adult mouse bone marrow has been studied in detail, and multiple ILC progenitors have been characterized. ILCs are mostly tissue-resident cells that develop in the perinatal period. More recently, ILC progenitors have also been identified in peripheral tissues. In this review, we discuss the stepwise transcription factor-directed differentiation of mouse ILC progenitors into mature ILCs, the critical time windows in ILC development, and the contribution of bone marrow versus tissue ILC progenitors to the pool of mature ILCs in tissues.


Subject(s)
Lymphocytes/cytology , Lymphocytes/immunology , Animals , Core Binding Factor alpha Subunits/immunology , Cytokines/immunology , Epigenesis, Genetic , Humans , Immunity, Innate , Infections/immunology , Inflammation/immunology , Thymus Gland/immunology , Transcription Factors/immunology
3.
PLoS Pathog ; 16(12): e1009136, 2020 12.
Article in English | MEDLINE | ID: mdl-33370418

ABSTRACT

The level of CD40 expression on dendritic cells (DCs) plays a decisive role in disease protection during Leishmania donovani (LD) infection. However, current understanding of the molecular regulation of CD40 expression remains elusive. Using molecular, cellular and functional approaches, we identified a role for Runx1 and Runx3 transcription factors in the regulation of CD40 expression in DCs. In response to lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα) or antileishmanial drug sodium antimony gluconate (SAG), both Runx1 and Runx3 translocated to the nucleus, bound to the CD40 promoter and upregulated CD40 expression on DCs. These activities of Runx proteins were mediated by the upstream phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Notably, LD infection attenuated LPS- or TNFα-induced CD40 expression in DCs by inhibiting PI3K-Akt-Runx axis via protein tyrosine phosphatase SHP-1. In contrast, CD40 expression induced by SAG was unaffected by LD infection, as SAG by blocking LD-induced SHP-1 activation potentiated PI3K-Akt signaling to drive Runx-mediated CD40 upregulation. Adoptive transfer experiments further showed that Runx1 and Runx3 play a pivotal role in eliciting antileishmanial immune response of SAG-treated DCs in vivo by promoting CD40-mediated type-1 T cell responses. Importantly, antimony-resistant LD suppressed SAG-induced CD40 upregulation on DCs by blocking the PI3K-Akt-Runx pathway through sustained SHP-1 activation. These findings unveil an immunoregulatory role for Runx proteins during LD infection.


Subject(s)
CD40 Antigens/immunology , Core Binding Factor alpha Subunits/immunology , Dendritic Cells/immunology , Gene Expression Regulation/immunology , Leishmaniasis, Visceral/immunology , Animals , CD40 Antigens/biosynthesis , Cricetinae , Humans , Leishmania donovani/immunology , Mice , Mice, Inbred BALB C
4.
Fish Shellfish Immunol ; 89: 228-236, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30936046

ABSTRACT

The Runx family is a kind of heteromeric transcription factors, which is defined by the presence of a runt domain. As transcriptional regulator during development and cell fate specification, Runx is best known for its critical roles in hematopoiesis. In the present study, a Runx transcription factor (designed as CgRunx) was identified and characterized from the oyster Crassostrea gigas. The complete coding sequence of CgRunx was of 1638 bp encoding a predicted polypeptide of 545 amino acids with one conserved runt domain, which shared high similarity with other reported Runx proteins. CgRunx was highly expressed in hemocytes, gill and mantle both at the protein and nucleic acid levels. CgRunx protein was localized specifically in the cell nuclei of hemocytes, and distributed at the tubule lumen of gill filament. During the larval developmental stages, the mRNA transcripts of CgRunx gradually increased after fertilization, reached to a relative high level at the 8 cell embryos and the blastula stage of 2-4 hpf (hours post fertilization) (about 40-fold), and peaked at early trochophore larvae (10 hpf) (about 60-fold). Whole-mount immunofluorescence assay further revealed that the abundant immunofluorescence signals of CgRunx distributed through the whole embryo at blastula stage (5 hpf), and progressively reduced with the development to a ring structure around the dorsal region in trochophore larvae (10 hpf). Scattered positive immunoreactivity signals finally appeared in the velum region of D-veliger larvae. After LPS and Vibrio splendidus stimulations, the expression levels of CgRunx mRNA in hemocytes were up-regulated significantly compared with that in the control (0 h), which were 2.98- and 2.46-fold (p < 0.05), 2.67- and 1.5-fold (p < 0.05), 2.36- and 1.38-fold (p < 0.05) at 3 h, 6 h and 12 h, respectively. These results collectively suggested that CgRunx involved in immune response and might participate in larvae hematopoiesis in oyster.


Subject(s)
Core Binding Factor alpha Subunits/genetics , Core Binding Factor alpha Subunits/immunology , Crassostrea/genetics , Crassostrea/immunology , Gene Expression Regulation/immunology , Immunity, Innate/genetics , Amino Acid Sequence , Animals , Core Binding Factor alpha Subunits/chemistry , Gene Expression Profiling , Sequence Alignment
5.
Adv Exp Med Biol ; 962: 395-413, 2017.
Article in English | MEDLINE | ID: mdl-28299670

ABSTRACT

During hematopoiesis, a variety of cells are generated from stem cells through successive rounds of cell fate determination processes. Studies in the last two decades have demonstrated the involvement of Runx transcription factor family members in differentiation of multiple types of hematopoietic cells. Along with evolutionary conservation, the Runx family is considered to be one of the ancestral regulators of hematopoiesis. It is conceivable that the Runx family is involved in shaping the immune system, which is then comprised of innate and acquired lymphoid cells in vertebrates. In this chapter, we will first summarize roles of Runx proteins during the development of T- and B-lymphocytes, which appeared later during evolution and express antigen specific receptors as a result of DNA recombination processes. We also discuss the recent findings that have unraveled the functions of Runx during differentiation of innate lymphoid cells (ILCs).


Subject(s)
B-Lymphocytes/immunology , Cell Differentiation/immunology , Core Binding Factor alpha Subunits/immunology , Lymphocytes/immunology , T-Lymphocytes/immunology , Animals , Hematopoiesis/immunology , Humans
6.
Int Immunopharmacol ; 28(2): 813-7, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25864621

ABSTRACT

CD4(+) helper T cells and CD8(+) cytotoxic T cells form the two major subsets of peripheral T lymphocytes. Helper T cells fulfill crucial roles in the activation and coordination of the immune response, while cytotoxic T cells kill virus-infected or tumor cells. Recent data suggest that the lineage identify of helper T cells is not fixed and that CD4(+) T cells under certain physiological conditions can be reprogrammed to express CD8 lineage genes and to develop into intestinal intraepithelial CD4(+) cytotoxic T lymphocytes that lack the expression of the key helper T cell lineage commitment factor ThPOK. Moreover, the analysis of mice with a conditional deletion of the transcription factor ThPOK or the histone deacetylases HDAC1 and HDAC2 indicated that CD8 lineage genes are actively repressed in CD4(+) T cells in order to maintain the lineage integrity of helper T cells. In this review I summarize recent studies that indicate plasticity of CD4(+) T cells towards a CTL program and that demonstrate that ThPOK and HDAC1-HDAC2 are part of a transcriptional regulatory circuit that counteracts the activity of the transcription factor Runx3 to maintain CD4(+) T cell lineage integrity.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , Cell Plasticity , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cell Lineage , Core Binding Factor alpha Subunits/immunology , DNA-Binding Proteins/immunology , Histone Deacetylase 1/immunology , Histone Deacetylase 2/immunology , Humans , Intestines/immunology , Transcription Factors/immunology
7.
Nat Rev Cancer ; 15(2): 81-95, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25592647

ABSTRACT

RUNX proteins belong to a family of metazoan transcription factors that serve as master regulators of development. They are frequently deregulated in human cancers, indicating a prominent and, at times, paradoxical role in cancer pathogenesis. The contextual cues that direct RUNX function represent a fast-growing field in cancer research and could provide insights that are applicable to early cancer detection and treatment. This Review describes how RUNX proteins communicate with key signalling pathways during the multistep progression to malignancy; in particular, we highlight the emerging partnership of RUNX with p53 in cancer suppression.


Subject(s)
Core Binding Factor alpha Subunits/genetics , Neoplasms/genetics , Tumor Suppressor Protein p53/metabolism , ADP-Ribosylation Factors/metabolism , Cell Differentiation/genetics , Cell Proliferation/genetics , Core Binding Factor alpha Subunits/immunology , Core Binding Factor alpha Subunits/metabolism , Cyclin-Dependent Kinases/metabolism , DNA Damage/genetics , DNA Methylation , DNA Repair/genetics , Humans , Inflammation/immunology , Phosphorylation , Signal Transduction/genetics , Transcription, Genetic/genetics
9.
Immunol Res ; 59(1-3): 45-55, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24847765

ABSTRACT

Transcription factors have recurring roles during T cell development and activation. Tcf1 and Lef1 are known to be essential for early stages of thymocyte maturation. Recent research has revealed several novel aspects of their functionality. Tcf1 is induced at the very earliest step of specifying hematopoietic progenitors to the T cell lineage as a key target gene downstream of Notch activation. In addition to promoting maturation of T-lineage-committed thymocytes, Tcf1 functions as a tumor suppressor in developing thymocytes, and this is mediated, paradoxically, by restraining Lef1 expression. After positive selection, Tcf1 and Lef1 act together to direct CD4(+)CD8(+) double positive thymocytes to a CD4(+) T cell fate. Although not required for CD8(+) T cell differentiation, Tcf1 and Lef1 cooperate with Runx factors to achieve stable silencing of the Cd4 gene in CD8(+) T cells. Tcf1 is also found to have versatile roles in innate immune cells, which partly mirror its functions in mature T helper cells. Discrepancy in requirements of Tcf1/Lef1 and ß-catenin in T cells has been a long-standing enigma. We will review other protein factors interacting with Tcf1 and Lef1 and discuss their regulatory roles independent of ß-catenin.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Hepatocyte Nuclear Factor 1-alpha/immunology , Immunity, Innate/physiology , Lymphoid Enhancer-Binding Factor 1/immunology , Animals , CD4 Antigens/immunology , Core Binding Factor alpha Subunits/immunology , Humans , Portraits as Topic , Thymocytes/immunology , beta Catenin/immunology
10.
Int Immunol ; 23(9): 553-63, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21750145

ABSTRACT

The mouse TCRγ locus is positively regulated by the transcription factors STAT5 and Runx. While the locus undergoes frequent rearrangements in T lymphocytes, TCRγ transcription is repressed in αß T cells. This phenomenon, known as TCRγ silencing, depends on pre-TCR-induced thymocyte proliferation. The molecular basis for TCRγ silencing, however, is largely unknown. Here, we show that pre-TCR signaling reduces transcription and histone acetylation of the TCRγ locus irrespective of V-J rearrangements. We also demonstrate that Runx is recruited to Eγ and HsA enhancer elements of the TCRγ locus, primarily at the CD4(-)CD8(-) double-negative stage and that Runx binding to these elements decreases at later stages of thymocyte development. Importantly, anti-CD3 antibody treatment decreased IL-7R expression levels, STAT5 phosphorylation and recruitment of STAT5 and Runx to Eγ and HsA elements in RAG2-deficient thymocytes, suggesting that pre-TCR signaling triggers reduced binding of STAT5 and Runx to the enhancer elements. Furthermore, we observed that misexpression of STAT5 or Runx in the CD4(+)CD8(+) double-positive cell line DPK induces TCRγ gene transcription. Finally, we showed that TCRγ transcription is induced in αß T cells from Runx3 transgenic mice, suggesting that Runx3 counteracts TCRγ silencing in αß T cells in vivo. Our results suggest that pre-TCR signaling indirectly inactivates TCRγ enhancers by reducing recruitment of STAT5 and Runx and imply that this effect is an important step for TCRγ silencing in αß T cells.


Subject(s)
Core Binding Factor alpha Subunits/metabolism , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , STAT5 Transcription Factor/metabolism , Thymocytes/metabolism , Animals , Core Binding Factor alpha Subunits/genetics , Core Binding Factor alpha Subunits/immunology , DNA-Binding Proteins/genetics , Enhancer Elements, Genetic/genetics , Gene Silencing/immunology , Genes, T-Cell Receptor gamma , Mice , Mice, Inbred C57BL , Mice, Knockout , Protein Binding/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/immunology , Receptors, Antigen, T-Cell, gamma-delta/genetics , Receptors, Antigen, T-Cell, gamma-delta/immunology , Receptors, Interleukin-7/genetics , STAT5 Transcription Factor/genetics , STAT5 Transcription Factor/immunology , Thymocytes/cytology , Thymocytes/immunology , Transcriptional Activation/genetics , Transgenes/genetics
11.
Immunity ; 34(3): 303-14, 2011 Mar 25.
Article in English | MEDLINE | ID: mdl-21435585

ABSTRACT

T cell fate is associated with mutually exclusive expression of CD4 or CD8 in helper and cytotoxic T cells, respectively. How expression of one locus is temporally coordinated with repression of the other has been a long-standing enigma, though we know RUNX transcription factors activate the Cd8 locus, silence the Cd4 locus, and repress the Zbtb7b locus (encoding the transcription factor ThPOK), which is required for CD4 expression. Here we found that nuclear organization was altered by interplay among members of this transcription factor circuitry: RUNX binding mediated association of Cd4 and Cd8 whereas ThPOK binding kept the loci apart. Moreover, targeted deletions within Cd4 modulated CD8 expression and pericentromeric repositioning of Cd8. Communication between Cd4 and Cd8 thus appears to enable long-range epigenetic regulation to ensure that expression of one excludes the other in mature CD4 or CD8 single-positive (SP) cells.


Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Core Binding Factor alpha Subunits/immunology , Gene Expression Regulation/immunology , Animals , Epigenomics , Flow Cytometry , In Situ Hybridization, Fluorescence , Mice , Mice, Inbred C57BL
12.
Adv Immunol ; 104: 1-23, 2009.
Article in English | MEDLINE | ID: mdl-20457114

ABSTRACT

Members of the Runx family of transcription factors, Runx1-3, are essential regulators of the immune system: a deficiency in one of the members, Runx1, results in complete ablation of hematopoiesis, and all three Runx proteins play important, nonredundant roles in immune system development and function. Here, we review gene regulation by Runx proteins in T lymphocytes, with a focus on their recently emerging roles in the development and function of peripheral CD4+ and CD8+ T lineages.


Subject(s)
Core Binding Factor alpha Subunits/immunology , Gene Expression Regulation , T-Lymphocytes/immunology , Animals , Cell Differentiation , Cell Lineage , Humans , T-Lymphocytes/cytology , T-Lymphocytes/metabolism
13.
Nat Immunol ; 9(10): 1131-9, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18776905

ABSTRACT

The transcription factor ThPOK is required and sufficient for the generation of CD4(+)CD8(-) thymocytes, yet the mechanism by which ThPOK orchestrates differentiation into the CD4(+) helper T cell lineage remains unclear. Here we used reporter mice to track the expression of transcription factors in developing thymocytes. Distal promoter-driven expression of the gene encoding the transcription factor Runx3 was restricted to major histocompatibility complex (MHC) class I-selected thymocytes. In ThPOK-deficient mice, such expression was derepressed in MHC class II-selected thymocytes, which contributed to their redirection to the CD8(+) T cell lineage. In the absence of both ThPOK and Runx, redirection was prevented and cells potentially belonging to the CD4(+) lineage, presumably specified independently of ThPOK, were generated. Our results suggest that MHC class II-selected thymocytes are directed toward the CD4(+) lineage independently of ThPOK but require ThPOK to prevent Runx-dependent differentiation toward the CD8(+) lineage.


Subject(s)
Cell Differentiation/immunology , Cell Lineage/immunology , Core Binding Factor alpha Subunits/immunology , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Helper-Inducer/cytology , Transcription Factors/immunology , Animals , Core Binding Factor alpha Subunits/metabolism , Flow Cytometry , Gene Expression , Gene Expression Regulation/immunology , Genes, Reporter , Histocompatibility Antigens Class II/immunology , Immunoblotting , Mice , Mice, Knockout , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Helper-Inducer/immunology
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