scholarly journals Lack of Foxp3 function and expression in the thymic epithelium

2007 ◽  
Vol 204 (3) ◽  
pp. 475-480 ◽  
Author(s):  
Adrian Liston ◽  
Andrew G. Farr ◽  
Zhibin Chen ◽  
Christophe Benoist ◽  
Diane Mathis ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Epithelial Cells ◽  
Cell Population ◽  
Cell Lineage ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelium ◽  
Thymocyte Differentiation ◽  
Necessary And Sufficient

Foxp3 is essential for the commitment of differentiating thymocytes to the regulatory CD4+ T (T reg) cell lineage. In humans and mice with a genetic Foxp3 deficiency, absence of this critical T reg cell population was suggested to be responsible for the severe autoimmune lesions. Recently, it has been proposed that in addition to T reg cells, Foxp3 is also expressed in thymic epithelial cells where it is involved in regulation of early thymocyte differentiation and is required to prevent autoimmunity. Here, we used genetic tools to demonstrate that the thymic epithelium does not express Foxp3. Furthermore, we formally showed that genetic abatement of Foxp3 in the hematopoietic compartment, i.e. in T cells, is both necessary and sufficient to induce the autoimmune lesions associated with Foxp3 loss. In contrast, deletion of a conditional Foxp3 allele in thymic epithelial cells did not result in detectable changes in thymocyte differentiation or pathology. Therefore, in mice the only known role for Foxp3 remains promotion of T reg cell differentiation within the T cell lineage, whereas there is no role for Foxp3 in thymic epithelial cells.

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 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 Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83

2016 ◽  
Vol 213 (9) ◽  
pp. 1685-1694 ◽  
Author(s):  
Julia von Rohrscheidt ◽  
Elisabetta Petrozziello ◽  
Jelena Nedjic ◽  
Christine Federle ◽  
Lena Krzyzak ◽  
...  
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Transmembrane Domain ◽  
Dendritic Cell Maturation ◽  
Functional Adaptation ◽  
Cd4 T Cell ◽  
Thymic Epithelial Cells ◽  
Cell Selection ◽  
Necessary And Sufficient ◽  
T Cell Selection

Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and –extrinsic functions through discrete protein domains, but it remains unclear how CD83’s capacity to operate through these alternative functional modules relates to its crucial role in TECs. In this study, using viral reconstitution of gene function in TECs, we found that CD83’s transmembrane domain is necessary and sufficient for thymic CD4 T cell selection. Moreover, a ubiquitination-resistant MHCII variant restored CD4 T cell selection in Cd83−/− mice. Although during dendritic cell maturation CD83 is known to stabilize MHCII through opposing the ubiquitin ligase March1, regulation of March1 did not account for CD83’s TEC-intrinsic role. Instead, we provide evidence that MHCII in cortical TECs (cTECs) is targeted by March8, an E3 ligase of as yet unknown physiological substrate specificity. Ablating March8 in Cd83−/− mice restored CD4 T cell development. Our results identify CD83-mediated MHCII stabilization through antagonism of March8 as a novel functional adaptation of cTECs for T cell selection. Furthermore, these findings suggest an intriguing division of labor between March1 and March8 in controlling inducible versus constitutive MHCII expression in hematopoietic antigen-presenting cells versus TECs.

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 T cell development in normal and thymopentin-treated nude mice.

1982 ◽  
Vol 156 (4) ◽  
pp. 1057-1064 ◽  
Author(s):  
G E Ranges ◽  
G Goldstein ◽  
E A Boyse ◽  
M P Schield
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Population ◽  
Nude Mice ◽  
T Cell Development ◽  
T Cell Differentiation ◽  
Athymic Mice ◽  
Germ Free

The extent and diversity of T cell differentiation in nude athymic mice are matters of dispute. In this study, we examined the splenic T cell population of pathogen-free and germ-free nu/nu mice, treated or not treated with the pentapeptide analogue of thymopoietin (TP-5), in terms of TL, Qa-1, and Lyt phenotypes. At all ages, 50-60% of nu/nu splenocytes, enriched for T lymphocytes by removal of sIg+ cells, expressed T markers, as compared with greater than 85% in normal mice. At 2 mo of age, all nu/nu splenic T cells expressed the surface phenotype TL+:Thy-1+:Ly-123. This is abnormal in two respects: first, because expression of TL is normally confined to thymocytes; and second, because there was no evidence of the usual diversification into the subsets Ly-1 and Ly-23. From 10 wk of age onwards, diversification into Ly subsets was evident in nu/nu spleen, although the usual predominance of Ly-1 over Ly-123 cells was not attained, and some TL+ cells persisted. Also, the ratio of Qa-1+ to Qa-1- cells rose progressively to as high as 4:1 at 4-6 mo, in contrast to the usual ratio of approximately 1:1, regardless of age. In the spleens of nu/nu mice treated with TP-5 from 5-8 weeks of age and tested 1 wk later, the proportion of T cells was raised, though not to normal levels, the number of TL+ cells was reduced, and there was diversification into Ly sets.

scholarly journals Differential effects of γc cytokines on postselection differentiation of CD8 thymocytes

Blood ◽  
2013 ◽  
Vol 121 (1) ◽  
pp. 107-117 ◽  
Author(s):  
Moutih Rafei ◽  
Alexandre Rouette ◽  
Sylvie Brochu ◽  
Juan Ruiz Vanegas ◽  
Claude Perreault
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Positive Selection ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Thymic Epithelial Cells ◽  
Double Positive

Abstract The primary consequence of positive selection is to render thymocytes responsive to cytokines and chemokines expressed in the thymic medulla. In the present study, our main objective was to discover which cytokines could support the differentiation of positively selected thymocytes. To this end, we have developed an in vitro model suitable for high-throughput analyses of positive selection and CD8 T-cell differentiation. The model involves coculture of TCRhiCD5intCD69− double-positive (DP) thymocytes with peptide-pulsed OP9 cells and γc-cytokines. We report that IL-4, IL-7, and IL-21 have nonredundant effects on positively selected DP thymocytes. IL-7 signaling phosphorylates STAT5 and ERK; induces Foxo1, Klf2, and S1pr1; and supports the differentiation of classic CD8 T cells. IL-4 activates STAT6 and ERK and supports the differentiation of CD8intPD-L1hiCD44hiEOMES+ innate CD8 T cells. IL-21 is produced by thymic epithelial cells and the IL-21 receptor-α is strongly induced on DP thymocytes undergoing positive selection. IL-21 signaling phosphorylates STAT3 and STAT5, but not ERK, and does not support CD8 T-cell differentiation. However, IL-21 has a unique ability to up-regulate BCL-6, expand DP thymocytes undergoing positive selection, and increase the production of mature T cells. Our data suggest that injection of recombinant IL-21 might enhance thymic output in subjects with age- or disease-related thymic atrophy.

scholarly journals Differentiation of a CD4/CD8αβ Double Positive T Cell Population from the CD8 Pool Is Both Predictive and Sufficient to Mediate Graft-Vs-Host Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2761-2761
Author(s):  
Nicholas J. Hess ◽  
David Turicek ◽  
Amy Hudson ◽  
Peiman Hematti ◽  
Jenny Gumperz ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Population ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Cell Populations ◽  
Human T Cell

Abstract Acute graft-vs-host disease (aGVHD) and cancer relapse remain the primary complications following an allogeneic hematopoietic stem cell transplantation (allo-HSCT) for malignant blood disorders. While post-transplant cyclophosphamide combined with standard GVHD prophylaxis has greatly reduced the overall prevalence and severity of aGVHD, relapse rates remain a concern. There is thus a need to identify the specific human T cell populations mediating GVHD vs GVL activity as a means to develop targeted therapeutics capable of controlling aGVHD without inhibiting GVL activity. In this study, we identify a novel human T cell population that develops after transplant that is predictive and sufficient for GVHD pathology. To determine the role of human T cell populations in aGVHD, we performed xenogeneic transplantation studies using primary human graft tissue from a variety of sources (peripheral blood, G-CSF mobilized peripheral blood, bone marrow and umbilical cord blood) in addition to collecting primary human aGVHD blood samples from our clinic. Using the LD50 dose of human graft tissue, we identified a novel mature CD4 +/CD8αβ + double positive (DP) T cell population that only developed after transplantation. The development of this population was further confirmed in aGVHD patients from our clinic. The presence of DP T cells, irrespective of graft source, was also predictive of lethal GVHD in as early as one week after xenogeneic transplantation. To identify the origin of DP T cells, we transplanted isolated human CD4 or CD8 T cells into mice which showed that DP T cells only arise from the CD8 pool. Furthermore, re-transplantation of flow-sorted CD8 T cells from GVHD mice did not reveal a 2nd wave of DP T cell differentiation. This data, in addition to their highly proliferative state, suggests that DP T cells represent highly activated CD8 T cell clones. The ability of these CD8-derived DP T cells to gain CD4 expression coincides with their co-expression of both RUNX3 and THPOK, the master transcription factors of the CD8 and CD4 lineages respectively, that classically repress each other. Intracellular cytokine staining also revealed that DP T cells are the primary activated T cell population in xenogeneic GVHD, secreting both modulatory and cytotoxic cytokines (e.g. IFNγ, IL-17A, IL-22, perforin and granzyme). Ex vivo re-stimulation or re-transplantation of flow-sorted DP T cells showed that this T cell population is capable of dividing and expanding independent of CD4 and CD8 single positive T cells with the majority of the isolated DP T cells retaining their co-expression of CD4 and CD8. Finally, transplantation of either isolated human peripheral blood CD4 or CD8 T cell populations were capable of causing lethal GVHD. Conversely, re-transplantation of flow-sorted DP, CD8 or CD4 T cells from GVHD mice revealed that DP and CD4 T cells are sufficient to mediate GVHD pathology but re-transplanted CD8 T cell are not. This correlates with the absence of DP T cell differentiation in that re-transplanted CD8 population. The differentiation of DP T cells from chronically activated CD8 T cells represents a novel mechanism of GVHD pathology not previously described. The presence of DP T cells in other chronic inflammatory human diseases also suggests a broader pathology mediated by DP T cells. Further understanding of DP T cell differentiation and pathology may lead to targeted prophylaxis and/or treatment regimens for aGVHD and other human chronic inflammatory diseases. Figure 1 Figure 1. Disclosures Capitini: Nektar Therapeutics: Honoraria; Novartis: Honoraria.

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