scholarly journals Adhesion of Immature and Mature T Cells Induces in Human Thymic Epithelial Cells (TEC) Activation of IL-6 Gene Trascription Factors (NF-κB And NF-IL6) and IL-6 Gene Expression: Role of αtβ1 and α6β4 Integrins

2000 ◽  
Vol 7 (2-4) ◽  
pp. 195-208 ◽  
Author(s):  
Emma Fiorini ◽  
Pier Carlo Marchisio ◽  
Maria Teresa Scupoli ◽  
Ornella Poffe ◽  
Elda Tagliabue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Close Contact ◽  
Cell Types ◽  
Binding Activity ◽  
Thymic Epithelial Cells ◽  
Cell Contact ◽  
Β4 Integrin

T cell precursors homed to thymus develop in close contact with stromal cells. Among them, thymic epithelial cells (TEC) are known to exert dominant roles in their survival and functional shaping. Key molecules mediating TEC/thymocytes interactions include cytokines and growth factors secreted by the two cell types and adhesion receptors mediating cell contact. Signaling events triggered in thymocytes by adhesion to epithelial cells have been extensively investigated, whereas little is known on the opposite phenomenon. We have previously investigated this issue in a co-culture system composed of TEC cultures derived from human normal thymus and heterologous thymocytes. We demonstrated that thymocytes adhere to TEC involving β1 and β4 integrins and induce the clustering of (α3β1 and α6β4 heterodimers at the TEC surface. In addition thymocyte adhesion was followed by activation of NF-κB and NF-IL6 gene transciption factors and enhanced IL-6 production. The two latter phenomena were reproduced by the cross-linking of the α3, α6, β1 and β4 integrins, thus implying that the α3β1 and α6β4 heterodimers can signal during thymocyte adhesion. We have extended our previous work investigating in the same experimental setting the inducing activity of non stimulated or activated policlonal or clonal mature T cells as representative of the more mature thymocyte subset. We found that adhesion of unstimulated T cell i) involved β1, but not β4 integrin functions at the surface ii) induced the clustering of α3β1 , but not α2β1 heterodimers at the TEC surface and iii) up-regulated the nuclear binding activity of NF-κB transcription factor and the IL-6 secretion. We propose that α3β1 and α6β4 heterodimers are induced to cluster at the TEC surface recognizing yet unknown cellular ligands differentially expressed during T cell development.

scholarly journals Fine-tuning of β-catenin in thymic epithelial cells is required for postnatal T cell development

2021 ◽  
Author(s):  
Sayumi Fujimori ◽  
Izumi Ohigashi ◽  
Hayato Abe ◽  
M Mark Taketo ◽  
Yousuke Takahama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
T Cell Development ◽  
Cell Development ◽  
Fine Tuning ◽  
Thymic Epithelial Cells ◽  
Loss Of Function ◽  
Thymic Epithelium

In the thymus, the thymic epithelium provides a microenvironment essential for the development of functionally competent and self-tolerant T cells. Previous findings showed that modulation of Wnt/β-catenin signaling in thymic epithelial cells (TECs) disrupts embryonic thymus organogenesis. However, the role of β-catenin in TECs for postnatal T cell development remains to be elucidated. Here, we analyzed gain-of function (GOF) and loss-of-function (LOF) of β-catenin highly specific in TECs. We found that GOF of β-catenin in TECs results in severe thymic dysplasia and T cell deficiency beginning from the embryonic period. By contrast, LOF of β-catenin in TECs reduces the number of cortical TECs and thymocytes modestly and only postnatally. These results indicate that fine-tuning of β-catenin expression within a permissive range is required for TECs to generate an optimal microenvironment to support postnatal T cell development.

scholarly journals Gastric Hyperplasia and Increased Proliferative Responses of Lymphocytes in Mice Lacking the COOH-terminal Ankyrin Domain of NF-κB2

1997 ◽  
Vol 186 (7) ◽  
pp. 999-1014 ◽  
Author(s):  
Hideaki Ishikawa ◽  
Daniel Carrasco ◽  
Estefania Claudio ◽  
Rolf-Peter Ryseck ◽  
Rodrigo Bravo
Keyword(s):  
T Cells ◽  
Lymphocyte Proliferation ◽  
Cytokine Production ◽  
Cell Types ◽  
Homozygous Deletion ◽  
Binding Activity ◽  
Activated T Cells ◽  
Physiological Relevance

The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative subunit of NF-κB, the p100 precursor is believed to function as an inhibitor of Rel/NF-κB activity by cytoplasmic retention of Rel/NF-κB complexes, like other members of the IκB family. However, the physiological relevance of the p100 precursor as an IκB molecule has not been understood. To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-κB2 (p100−/−) had marked gastric hyperplasia, resulting in early postnatal death. p100−/− animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic induction of nuclear κB–binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-κB complexes in various cell types and its absence cannot be efficiently compensated for by other IκB proteins.

scholarly journals High Dimensional Tissue-Based Spatial Analysis of the Tumor Microenvironment of Follicular Lymphoma Reveals Unique Immune Niches inside Malignant Follicles

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Jose C Villasboas ◽  
Patrizia Mondello ◽  
Angelo Fama ◽  
Melissa C. Larson ◽  
Andrew L. Feldman ◽  
...  
Keyword(s):  
T Cells ◽  
Spatial Distribution ◽  
T Cell ◽  
B Cells ◽  
Research Funding ◽  
Memory T Cells ◽  
Cell Types ◽  
T Cell Subsets ◽  
Cell Contact ◽  
Private Company

Background The importance of the immune system in modulating the trajectory of lymphoma outcomes has been increasingly recognized. We recently showed that CD4+ cells are associated with clinical outcomes in a prospective cohort of almost 500 patients with follicular lymphoma (FL). Specifically, we showed that the absence of CD4+ cells inside follicles was independently associated with increased risk of early clinical failure. These data suggest that the composition, as well as the spatial distribution of immune cells within the tumor microenvironment (TME), play an important role in FL. To further define the architecture of the TME in FL we analyzed a FL tumor section using the Co-Detection by Indexing (CODEX) multiplex immunofluorescence system. Methods An 8-micron section from a formalin-fixed paraffin-embedded block containing a lymph node specimen from a patient with FL was stained with a cocktail of 15 CODEX antibodies. Five regions of interest (ROIs) were imaged using a 20X air objective. Images underwent single-cell segmentation using a Unet neural network, trained on manually segmented cells (Fig 1A). Cell type assignment was done after scaling marker expression and clustering using Phenograph. Each ROI was manually masked to indicate areas inside follicles (IF) and outside follicles (OF). Relative and absolute frequencies of cell types were calculated for each region. Cellular contacts were measured as number and types of cell-cell contacts within two cellular diameters. To identify proximity communities, we clustered cells based on number and type of neighboring masks using Phenograph. The number of cell types and cellular communities were calculated inside and outside follicles after adjustment for total IF and OF areas. The significance of cell contact was measured using a random permutation test. Results We identified 13 unique cell subsets (11 immune, 1 endothelial, 1 unclassified) in the TME of our FL section (Fig. 1A). The unique phenotype of each subset was confirmed using a dimensionality reduction tool (t-SNE). The global composition of the TME varied minimally across ROIs and consisted primarily of B cells, T cells, and macrophages subsets - in decreasing order of frequency. Higher spatial heterogeneity across ROIs was observed in the frequency of T cell subsets in comparison to B cells subsets. Inspecting the spatial distribution of T cell subsets (Fig. 1B), we observed that cytotoxic T cells were primarily located in OF areas, whereas CD4+ T cells were found in both IF and OF areas. Notably, the majority of CD4+ T cells inside the follicles expressed CD45RO (memory phenotype), while most of the CD4+ T cells outside the follicles did not. Statistical analysis of the spatial distribution of CD4+ memory T cell subsets confirmed a significant increase in their frequency inside follicles compared to outside (20.4% vs 11.2%, p < 0.001; Fig. 1D). Cell-cell contact analysis (Fig 1C) showed increased homotypic contact for all cell types. We also found a higher frequency of heterotypic contact between Ki-67+CD4+ memory T cells and Ki-67+ B cells. Pairwise analysis showed these findings were statistically significant, indicating these cells are organized in niches rather than randomly distributed across image. Analysis of cellular communities (Fig. 1C) identified 13 niches, named according to the most frequent type of cell-cell contact. All CD4+ memory T cell subsets were found to belong to the same neighborhood (CD4 Memory community). Analysis of the spatial distribution of this community confirmed that these niches were more frequently located inside follicles rather than outside (26.3±4% vs 0.004%, p < 0.001, Fig. 1D). Conclusions Analysis of the TME using CODEX provides insights on the complex composition and unique architecture of this FL case. Cells were organized in a pattern characterized by (1) high degree of homotypic contact and (2) increased heterotypic interaction between activated B cells and activated CD4+ memory T cells. Spatial analysis of both individual cell subsets and cellular neighborhoods demonstrate a statistically significant increase in CD4+ memory T cells inside malignant follicles. This emerging knowledge about the specific immune-architecture of FL adds mechanistic details to our initial observation around the prognostic value of the TME in this disease. These data support future studies using modulation of the TME as a therapeutic target in FL. Figure 1 Disclosures Galkin: BostonGene: Current Employment, Patents & Royalties. Svekolkin:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Postovalova:BostonGene: Current Employment, Current equity holder in private company. Bagaev:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Ovcharov:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Varlamova:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Novak:Celgene/BMS: Research Funding. Witzig:AbbVie: Consultancy; MorphSys: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Nowakowski:Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Ansell:Trillium: Research Funding; Takeda: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; AI Therapeutics: Research Funding; ADC Therapeutics: Research Funding.

scholarly journals Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis

2006 ◽  
Vol 203 (1) ◽  
pp. 189-201 ◽  
Author(s):  
Ronit Vogt Sionov ◽  
Orly Cohen ◽  
Shlomit Kfir ◽  
Yael Zilberman ◽  
Eitan Yefenof
Keyword(s):  
T Cell ◽  
Glucocorticoid Receptor ◽  
Cell Lines ◽  
Cell Types ◽  
Thymic Epithelial Cells ◽  
Dependent Manner ◽  
Localization Signal ◽  
Induced Apoptosis ◽  
T Cell Lines

The mechanisms by which glucocorticoid receptor (GR) mediates glucocorticoid (GC)-induced apoptosis are unknown. We studied the role of mitochondrial GR in this process. Dexamethasone induces GR translocation to the mitochondria in GC-sensitive, but not in GC-resistant, T cell lines. In contrast, nuclear GR translocation occurs in all cell types. Thymic epithelial cells, which cause apoptosis of the PD1.6 T cell line in a GR-dependent manner, induce GR translocation to the mitochondria, but not to the nucleus, suggesting a role for mitochondrial GR in eliciting apoptosis. This hypothesis is corroborated by the finding that a GR variant exclusively expressed in the mitochondria elicits apoptosis of several cancer cell lines. A putative mitochondrial localization signal was defined to amino acids 558–580 of human GR, which lies within the NH2-terminal part of the ligand-binding domain. Altogether, our data show that mitochondrial and nuclear translocations of GR are differentially regulated, and that mitochondrial GR translocation correlates with susceptibility to GC-induced apoptosis.

scholarly journals Cathepsin L Regulates CD4+ T Cell Selection Independently of Its Effect on Invariant Chain

2002 ◽  
Vol 195 (10) ◽  
pp. 1349-1358 ◽  
Author(s):  
Karen Honey ◽  
Terry Nakagawa ◽  
Christoph Peters ◽  
Alexander Rudensky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Positive Selection ◽  
Cathepsin L ◽  
Cd4 T Cell ◽  
Thymic Epithelial Cells ◽  
Invariant Chain ◽  
Cell Selection ◽  
T Cell Selection

CD4+ T cells are positively selected in the thymus on peptides presented in the context of major histocompatibility complex class II molecules expressed on cortical thymic epithelial cells. Molecules regulating this peptide presentation play a role in determining the outcome of positive selection. Cathepsin L mediates invariant chain processing in cortical thymic epithelial cells, and animals of the I-Ab haplotype deficient in this enzyme exhibit impaired CD4+ T cell selection. To determine whether the selection defect is due solely to the block in invariant chain cleavage we analyzed cathepsin L–deficient mice expressing the I-Aq haplotype which has little dependence upon invariant chain processing for peptide presentation. Our data indicate the cathepsin L defect in CD4+ T cell selection is haplotype independent, and thus imply it is independent of invariant chain degradation. This was confirmed by analysis of I-Ab mice deficient in both cathepsin L and invariant chain. We show that the defect in positive selection in the cathepsin L−/− thymus is specific for CD4+ T cells that can be selected in a wild-type and provide evidence that the repertoire of T cells selected differs from that in wild-type mice, suggesting cortical thymic epithelial cells in cathepsin L knockout mice express an altered peptide repertoire. Thus, we propose a novel role for cathepsin L in regulating positive selection by generating the major histocompatibility complex class II bound peptide ligands presented by cortical thymic epithelial cells.

RB Controls Size, Cellularity, and T Cell Output of the Mouse Thymus

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 835-835
Author(s):  
Phillip M. Garfin ◽  
Patrick Viatour ◽  
Dullei Min ◽  
Jerrod Bryson ◽  
Kenneth I. Weinberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Conflicts Of Interest ◽  
Thymic Epithelial Cells ◽  
Main Function ◽  
Thymic Involution ◽  
Regulatory Relationship ◽  
Thymic Tissue ◽  
Rb Pathway

Abstract Abstract 835 The establishment of the thymic microenvironment early in life is crucial for the production functional T cells. Conversely, thymic involution results in a decreased T cell output. Thymic involution has important health implications especially following bone marrow transplant. Our objective is to determine molecular and cellular mechanisms that will allow for regeneration of involuted thymic tissue, restore production of naïve T cells, and improve immune function while improving our understanding of immunobiology. In this pursuit, we have focused on the Retinoblastoma family of tumor suppressor proteins. The main function of the RB pathway is to restrict passage through the G1/S transition of the cell cycle. RB and its two family members, p107 and p130, mediate the action of a broad range of cellular signals to control the proliferation, survival, and differentiation status of a large number of mammalian cell types. We found that inactivation of the RB pathway in the thymus by early deletion of RB family genes prevents thymic involution, promotes expansion of functional thymic epithelial cells (TECs), and increases thymic T cell output. Moreover, we have identified a direct regulatory relationship between RB and the Foxn1 transcription factor Via E2F transcription factors, where RB/E2F complexes directly repress the Foxn1 promoter, thereby promoting involution. Thus, the RB family is a critical mediator of extra- and intra-cellular signals to regulate thymic epithelial cells and thymus function, and decreasing RB pathway function may promote regeneration of the involuted thymus and restoration of naïve T cell production in patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Strong T cell tolerance in parent----F1 bone marrow chimeras prepared with supralethal irradiation. Evidence for clonal deletion and anergy.

1990 ◽  
Vol 171 (4) ◽  
pp. 1101-1121 ◽  
Author(s):  
E K Gao ◽  
D Lo ◽  
J Sprent
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Tolerance Induction ◽  
Thymic Epithelial Cells ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Cd4 Cells ◽  
Clonal Deletion ◽  
Host Type

T cell tolerance induction was examined in long-term H-2-heterozygous parent----F1 chimeras prepared with supralethal irradiation (1,300 rad). Although these chimeras appeared to be devoid of host-type APC, the donor T cells developing in the chimeras showed marked tolerance to host-type H-2 determinants. Tolerance to the host appeared to be virtually complete in four assay systems: (a) primary mixed lymphocyte reactions (MLR) of purified lymph node (LN) CD8+ cells (+/- IL-2); (b) primary MLR of CD4+ (CD8-) thymocytes; (c) skin graft rejection; and (d) induction of lethal graft-vs.-host disease by CD4+ cells. Similar tolerance was observed in chimeras given double irradiation. The only assay in which the chimera T cells failed to show near-total tolerance to the host was the primary MLR of post-thymic CD4+ cells. In this assay, LN CD4+ cells regularly gave a significant antihost MLR. The magnitude of this response was two- to fourfold less than the response of normal parental strain CD4+ cells and, in I-E(-)----I-E+ chimeras, was paralleled by approximately 70% deletion of V beta 11+ cells. Since marked tolerance was evident at the level of mature thymocytes, tolerance induction in the chimeras presumably occurred in the thymus itself. The failure to detect host APC in the thymus implies that tolerance reflected contact with thymic epithelial cells (and/or other non-BM-derived cells in the thymus). To account for the residual host reactivity of LN CD4+ cells and the incomplete deletion of V beta 11+ cells, it is suggested that T cell contact with thymic epithelial cells induced clonal deletion of most of the host-reactive T cells but spared a proportion of these cells (possibly low affinity cells). Since these latter cells appeared to be functionally inert in the thymus (in contrast to LN), we suggest that the thymic epithelial cells induced a temporary form of anergy in the remaining host-reactive thymocytes. This anergic state disappeared when the T cells left the thymus and reached LN.

scholarly journals The Early Postnatal Life: A Dynamic Period in Thymic Epithelial Cell Differentiation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruben G. R. Pinheiro ◽  
Nuno L. Alves
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cell ◽  
T Cell Development ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelial Cell ◽  
Postnatal Life ◽  
Functionally Diverse ◽  
Redundant Role

The microenvironments formed by cortical (c) and medullary (m) thymic epithelial cells (TECs) play a non-redundant role in the generation of functionally diverse and self-tolerant T cells. The role of TECs during the first weeks of the murine postnatal life is particularly challenging due to the significant augment in T cell production. Here, we critically review recent studies centered on the timely coordination between the expansion and maturation of TECs during this period and their specialized role in T cell development and selection. We further discuss how aging impacts on the pool of TEC progenitors and maintenance of functionally thymic epithelial microenvironments, and the implications of these chances in the capacity of the thymus to sustain regular thymopoiesis throughout life.

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