scholarly journals Foxp3 enhancers synergize to maximize regulatory T cell suppressive capacity

2021 ◽  
Vol 218 (8) ◽  
Author(s):  
Xinying Zong ◽  
Xiaolei Hao ◽  
Beisi Xu ◽  
Jeremy Chase Crawford ◽  
Shaela Wright ◽  
...  
Keyword(s):  
Foxp3 Expression ◽  
Regulatory Elements ◽  
Environmental Cues ◽  
Cell Repertoire ◽  
Intrinsic Factors ◽  
Receptor Repertoire ◽  
Suppressive Capacity ◽  
Extrinsic Cues ◽  
Cell Induction ◽  
Lineage Stability

T reg cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How their robust function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of T reg lineage–specifying factor Foxp3. Foxp3 enhancers are known as distinct readers of environmental cues controlling T reg cell induction or lineage stability. However, their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms determining Foxp3 expression and thereby T reg cell suppressive capacity uncertain. We examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize T reg cell induction, Foxp3 expression level, or lineage stability through distinct modes and that ablation of synergistic enhancers leads to lethal autoimmunity in young mice. Thus, the induction and maintenance of a diverse, stable T reg cell repertoire rely on combinatorial Foxp3 enhancers, suggesting broad, stage-specific, synergistic activities of cell-intrinsic factors and cell-extrinsic cues in determining T reg cell suppressive capacity.

scholarly journals The effects of microenvironment on the redifferentiation of regenerating neurones: neurite architecture, acetylcholine receptors and Ca2+ channel distribution

1987 ◽  
Vol 132 (1) ◽  
pp. 111-131
Author(s):  
M. E. Spira ◽  
D. Zeldes ◽  
B. Hochner ◽  
A. Dormann
Keyword(s):  
Action Potentials ◽  
Acetylcholine Receptors ◽  
Membrane Properties ◽  
Environmental Cues ◽  
Freezing And Thawing ◽  
Intrinsic Factors ◽  
Extrinsic Cues ◽  
Voltage Dependent ◽  
Synaptic Receptors ◽  
Ca2 Channels

Severed adult neurones, which are capable of regrowth, encounter different microenvironments from those encountered during development. Moreover, adult neurones may respond in a different manner from developing neurones to the same environmental cues. Thus, the recovery of the integrative and transmission capabilities (which depend on the neuronal architecture, passive and active membrane properties, and synaptic receptor distribution) by a regenerating adult neurone may not be complete. In the present review, we examine several aspects of the outcome of the interaction between the microenvironment and regrowing neurones using the cockroach giant interneurones (GINs) as a model system. We demonstrate that whereas extrinsic cues govern the morphological redifferentiation and distribution of synaptic receptors, the distribution of voltage-dependent Ca2+ channels is to a large extent determined by intrinsic factors. The pathway of regrowth and the architecture of regenerating GINs were studied by examination of intracellularly stained fibres. The environments provided by the connectives and ganglia are different. The elongating sprouts in the connective appeared as smooth cylinders. Within the ganglionic domain, the main longitudinal sprouts emitted neurites which extended and branched into the neuropile. The local cues for branching of neurites were eliminated by freezing and thawing of the ganglia prior to the arrival of the growing tips. The failure to extend neurites under these conditions is attributed to the elimination of extrinsic signals for morphological redifferentiation of the fibres, since the same fibres emit neurites in anterior ganglia which have not been subjected to freezing and thawing. The distribution of acetylcholine receptors (AChRs) on the GINs was mapped by ionophoretic application of ACh. In both the intact and regenerating GINs receptors were located only on the neurites. Freezing and thawing of a ganglion eliminated the local signals for insertion and/or activation of AChRs on the neurites. Thus, both the morphological redifferentiation and the distribution of AChRs are affected by the microenvironment. Voltage-dependent Ca2+ channels were detected after intracellular injection of tetraethylammonium into the GIN and in the presence of tetrodotoxin (TTX) and Ba2+ in the extracellular space. The regrowing axon tips always revealed large barium action potentials independent of the CNS microenvironment. This observation is consistent with the hypothesis that Ca2+ plays an important role in the growth process. However, increased Ba2+ responsiveness was also observed in axonal segments proximal to the region of neuronal extension.(ABSTRACT TRUNCATED AT 400 WORDS)

Initiation of facial motoneurone migration is dependent on rhombomeres 5 and 6

Development ◽  
2001 ◽  
Vol 128 (19) ◽  
pp. 3707-3716
Author(s):  
Michèle Studer
Keyword(s):  
Chick Embryo ◽  
Environmental Cues ◽  
Motor Nucleus ◽  
Migratory Behaviour ◽  
In Ovo ◽  
Intrinsic Factors ◽  
Extrinsic Cues ◽  
Facial Motor Nucleus ◽  
Migratory Path ◽  
Embryo Chick

In mammals, facial branchiomotor (FBM) neurones are born in ventral rhombomere (r) 4 and migrate through r5 to dorsal r6 where they form the facial motor nucleus. This pattern of migration gives rise to the distinctive appearance of the internal genu of the facial nerve, which is lacking in birds. To distinguish between extrinsic cues and intrinsic factors in the caudal migration of FBM neurones, this study takes advantage of the evolutionary migratory difference between mouse and chick in generating mouse-chick chimaeras in ovo. After the homotopic transplantation of mouse r5 and/or r6 into a chick embryo, chick ventral r4 neurones redirected their cell bodies towards the ectopic mouse source and followed a caudal migratory path, reminiscent of mouse FBM neurones. In a second series of grafting experiments, when mouse r4 was transplanted in place of chick r4, mouse r4 neurones were unable to migrate into chick r5, although mouse and chick cells were able to mix freely within r4. Thus, these data suggest that local environmental cues embedded in mouse r5 and r6 are directly involved in initiating caudal migration of FBM neurones. In addition, they demonstrate that chick FBM neurones are competent to recapitulate a migratory behaviour that has been lost during avian phylogeny.

scholarly journals Runx proteins regulate Foxp3 expression

2009 ◽  
Vol 206 (11) ◽  
pp. 2329-2337 ◽  
Author(s):  
Ludovica Bruno ◽  
Luca Mazzarella ◽  
Maarten Hoogenkamp ◽  
Arnulf Hertweck ◽  
Bradley S. Cobb ◽  
...  
Keyword(s):  
T Cells ◽  
Dna Binding ◽  
Cd4 T Cells ◽  
Target Genes ◽  
De Novo ◽  
Foxp3 Expression ◽  
Regulatory Elements ◽  
Dominant Negative ◽  
Downstream Target ◽  
Runx Proteins

Runx proteins are essential for hematopoiesis and play an important role in T cell development by regulating key target genes, such as CD4 and CD8 as well as lymphokine genes, during the specialization of naive CD4 T cells into distinct T helper subsets. In regulatory T (T reg) cells, the signature transcription factor Foxp3 interacts with and modulates the function of several other DNA binding proteins, including Runx family members, at the protein level. We show that Runx proteins also regulate the initiation and the maintenance of Foxp3 gene expression in CD4 T cells. Full-length Runx promoted the de novo expression of Foxp3 during inducible T reg cell differentiation, whereas the isolated dominant-negative Runt DNA binding domain antagonized de novo Foxp3 expression. Foxp3 expression in natural T reg cells remained dependent on Runx proteins and correlated with the binding of Runx/core-binding factor β to regulatory elements within the Foxp3 locus. Our data show that Runx and Foxp3 are components of a feed-forward loop in which Runx proteins contribute to the expression of Foxp3 and cooperate with Foxp3 proteins to regulate the expression of downstream target genes.

scholarly journals Deep sequencing of the T-cell receptor repertoire in CD8+ T-large granular lymphocyte leukemia identifies signature landscapes

Blood ◽  
2013 ◽  
Vol 122 (25) ◽  
pp. 4077-4085 ◽  
Author(s):  
Michael J. Clemente ◽  
Bartlomiej Przychodzen ◽  
Andres Jerez ◽  
Brittney E. Dienes ◽  
Manuel G. Afable ◽  
...  
Keyword(s):  
T Cell ◽  
Deep Sequencing ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Receptor Repertoire ◽  
Key Points ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire ◽  
Lgl Leukemia

Key PointsT-cell repertoire deep sequencing clearly identifies the nucleotide and amino acid sequence of the immunodominant clone in T-LGL leukemia patients. Deep-sequencing results suggest that CD8+ T-LGL leukemia is characterized by specific CDR3 clonotypes that are private to the disease.

scholarly journals Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity

2016 ◽  
Vol 113 (22) ◽  
pp. 6248-6253 ◽  
Author(s):  
Hidetoshi Nakagawa ◽  
Jessica M. Sido ◽  
Edwin E. Reyes ◽  
Valerie Kiers ◽  
Harvey Cantor ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Antitumor Immunity ◽  
Inflammatory Responses ◽  
Foxp3 Expression ◽  
Effector Cells ◽  
T Effector Cells ◽  
Surface Receptors ◽  
Enhanced Production ◽  
The Face ◽  
Lineage Stability

Expression of the transcription factor Helios by Tregs ensures stable expression of a suppressive and anergic phenotype in the face of intense inflammatory responses, whereas Helios-deficient Tregs display diminished lineage stability, reduced FoxP3 expression, and production of proinflammatory cytokines. Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment. Induction of an unstable Treg phenotype is associated with enhanced production of proinflammatory cytokines by tumor-infiltrating but not systemic Tregs and significantly delayed tumor growth. Ab-dependent engagement of Treg surface receptors that result in Helios down-regulation also promotes conversion of intratumoral but not systemic Tregs into T effector cells and leads to enhanced antitumor immunity. These findings suggest that selective instability and conversion of intratumoral CD4 Tregs through genetic or Ab-based targeting of Helios may represent an effective approach to immunotherapy.

scholarly journals Sperm entry induces polarity in fucoid zygotes

Development ◽  
2000 ◽  
Vol 127 (3) ◽  
pp. 493-501 ◽  
Author(s):  
W.E. Hable ◽  
D.L. Kropf
Keyword(s):  
Environmental Cues ◽  
Entry Site ◽  
Environmental Signals ◽  
Growth Axis ◽  
Low Sodium ◽  
Extrinsic Cues ◽  
Sperm Entry ◽  
Actin Patch ◽  
Adhesive Secretion ◽  
Lines Of Evidence

Fucoid zygotes establish a rhizoid-thallus growth axis in response to environmental signals; however, these extrinsic cues are not necessary for polarization, suggesting that zygotes may have inherent polarity. The hypothesis that sperm entry provides a default pathway for polarization of zygotes cultured in the absence of environmental signals was tested, and was supported by several lines of evidence. First, an F-actin patch, a cortical marker of the rhizoid pole, formed at the sperm entry site within minutes of fertilization. Second, the sperm entry site predicted the site of polar adhesive secretion (the first morphological manifestation of the rhizoid pole) and the position of rhizoid outgrowth. Third, when fertilization was restricted to one hemisphere of the egg, rhizoid outgrowth always occurred from that hemisphere. Fourth, delivery of sperm to one location within a population of eggs resulted in polarization of both adhesive secretion and rhizoid outgrowth toward the sperm source. Finally, induction of polyspermy using low sodium seawater increased the frequency of formation of two rhizoids. Sperm entry therefore provides an immediate default axis that can later be overridden by environmental cues.

Viral infection engenders bona fide and bystander lung memory B cell subsets through permissive selection

2021 ◽  
Author(s):  
Claude Gregoire ◽  
Lionel Spinelli ◽  
Sergio Villazala-Merino ◽  
Laurine Gil ◽  
Myriam Moussa ◽  
...  
Keyword(s):  
B Cell ◽  
Plasma Cells ◽  
Selection Process ◽  
Cell Receptor ◽  
Confocal Imaging ◽  
Antigen Specificity ◽  
Cell Repertoire ◽  
Fluorescent Reporter ◽  
Receptor Repertoire ◽  
Bona Fide

Lung-resident memory B cells (MBCs) provide localized protection against reinfection in the respiratory airways. Currently, the biology of these cells remains largely unexplored. Here, we combined influenza and SARS-CoV-2 infection with fluorescent-reporter mice to identify MBCs regardless of antigen specificity. scRNA-seq analysis and confocal imaging revealed that two main transcriptionally distinct subsets of MBCs colonize the lung peribronchial niche after infection. These subsets arise from different progenitors and are both class-switched, somatically mutated and intrinsically biased in their differentiation fate towards plasma cells. Combined analysis of antigen-specificity and B cell receptor repertoire unveiled a highly permissive selection process that segregates these subsets into bona fide virus-specific MBCs and bystander MBCs with no apparent specificity for eliciting viruses. Thus, diverse transcriptional programs in MBCs are not linked to specific effector fates but rather to divergent strategies of the immune system to simultaneously provide rapid protection from reinfection while diversifying the initial B cell repertoire.

scholarly journals Elevated N-glycosylation of immunoglobulin G variable regions in myasthenia gravis highlights a commonality across autoantibody-associated diseases

2021 ◽  
Author(s):  
Caleigh Mandel-Brehm ◽  
Miriam L. Fichtner ◽  
Ruoyi Jiang ◽  
Valerie J. Winton ◽  
Sara E. Vazquez ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Myasthenia Gravis ◽  
B Cell ◽  
Immunoglobulin G ◽  
Somatic Hypermutation ◽  
Gene Segment ◽  
Cell Repertoire ◽  
Variable Regions ◽  
Receptor Repertoire ◽  
Glycosylation Sites

AbstractElevated N-linked glycosylation of immunoglobulin G variable regions (IgG-VN-Glyc) is an emerging molecular phenotype associated with autoimmune disorders. To test the broader specificity of elevated IgG-VN-Glyc, we studied patients with distinct subtypes of myasthenia gravis (MG), a B cell-mediated autoimmune disease. Our experimental design included adaptive immune receptor repertoire sequencing to quantify and characterize N-glycosylation sites in the global B cell receptor repertoire, proteomics to examine glycosylation patterns of the circulating IgG, and production of human-derived recombinant autoantibodies, which were studied with mass spectrometry and antigen binding assays to confirm occupation of glycosylation sites and determine whether they alter binding. We found that the frequency of IgG-VN-Glyc motifs was increased in the B cell repertoire of MG patients when compared to healthy donors. Motifs were introduced by both biased V gene segment usage and somatic hypermutation. IgG-VN-Glyc could be observed in the circulating IgG in a subset of MG patients. Autoantigen binding, by patient-derived MG autoantigen-specific monoclonal antibodies with experimentally confirmed presence of IgG-VN-Glyc, was not altered by the glycosylation. Our findings extend prior work on patterns of variable region N-linked glycosylation in autoimmunity to MG subtypes. Although occupied IgG-VN-Glyc motifs are found on MG autoantigen-specific monoclonal antibodies, they are not required for binding to the autoantigen in this disease.

scholarly journals Analysis of T-Cell Receptor Repertoire in Transplantation: Fingerprint of T Cell-mediated Alloresponse

2022 ◽  
Vol 12 ◽  
Author(s):  
Guangyao Tian ◽  
Mingqian Li ◽  
Guoyue Lv
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Immune Monitoring ◽  
Antigen Specificity ◽  
Cell Repertoire ◽  
Receptor Repertoire ◽  
Cell Clones ◽  
Alloreactive T Cell

T cells play a key role in determining allograft function by mediating allogeneic immune responses to cause rejection, and recent work pointed their role in mediating tolerance in transplantation. The unique T-cell receptor (TCR) expressed on the surface of each T cell determines the antigen specificity of the cell and can be the specific fingerprint for identifying and monitoring. Next-generation sequencing (NGS) techniques provide powerful tools for deep and high-throughput TCR profiling, and facilitate to depict the entire T cell repertoire profile and trace antigen-specific T cells in circulation and local tissues. Tailing T cell transcriptomes and TCR sequences at the single cell level provides a full landscape of alloreactive T-cell clones development and biofunction in alloresponse. Here, we review the recent advances in TCR sequencing techniques and computational tools, as well as the recent discovery in overall TCR profile and antigen-specific T cells tracking in transplantation. We further discuss the challenges and potential of using TCR sequencing-based assays to profile alloreactive TCR repertoire as the fingerprint for immune monitoring and prediction of rejection and tolerance.

scholarly journals DNA Methyltransferase Inhibition Promotes Th1 Polarization in Human CD4+CD25high FOXP3+ Regulatory T Cells but Does Not Affect Their Suppressive Capacity

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Sija Landman ◽  
Marjan Cruijsen ◽  
Paulo C. M. Urbano ◽  
Gerwin Huls ◽  
Piet E. J. van Erp ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Dna Methyltransferase ◽  
Hematological Malignancies ◽  
Foxp3 Expression ◽  
Significant Inhibition ◽  
Naturally Occurring ◽  
Suppressive Capacity

Regulatory T cells (Treg) can show plasticity whereby FOXP3 expression, the master transcription factor for Treg suppressor function, is lost and proinflammatory cytokines are produced. Optimal FOXP3 expression strongly depends on hypomethylation of the FOXP3 gene. 5-Azacytidine (Aza) and its derivative 5-aza-2′-deoxycytidine (DAC) are DNA methyltransferase inhibitors (DNMTi) that are therapeutically used in hematological malignancies, which might be an attractive strategy to promote Treg stability. Previous in vitro research primarily focused on Treg induction by DAC from naïve conventional CD4+ T cells (Tconv). Here, we examined the in vitro effect of DAC on the stability and function of FACS-sorted human naturally occurring CD4+CD25high FOXP3+ Treg. We found that in vitro activation of Treg in the presence of DAC led to a significant inhibition of Treg proliferation, but not of Tconv. Although Treg activation in the presence of DAC led to increased IFNγ expression and induction of a Thelper-1 phenotype, the Treg maintained their suppressive capacity. DAC also induced a trend towards increased IL-10 expression. In vivo studies in patients with hematological malignancies that were treated with 5-azacytidine (Vidaza) supported the in vitro findings. In conclusion, despite its potential to increase IFNγ expression, DAC does preserve the suppressor phenotype of naturally occurring Treg.

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