Regulatory T (Treg) cells are pivotal for the maintenance of peripheral tolerance by controlling self-reactive, chronic, and homeostatic T-cell responses. Here, we report that the increase in ...Treg-cell suppressive function observed in lymphopenic mice correlates with the degree of lymphopenia and is caused by a higher frequency of a novel subpopulation of CD103(pos) ICOS(pos) Treg cells. Though present in the thymus, CD103(pos) ICOS(pos) Treg cells are not generated there but recirculate from the periphery to that site. The acquisition and maintenance of this distinctive phenotype requires the LN microenvironment and the in situ availability of antigen. Contrary to conventional effector and other Treg cells, the cellularity of CD103(pos) ICOS(pos) Treg cells is not affected by the absence of IL-7 and thymic stroma lymphopoetin. Given their increased frequency in lymphopenia, the absolute number of CD103(pos) ICOS(pos) Treg cells remains unchanged in the periphery irrespective of a paucity of total Treg cells. We furthermore demonstrate, with cell transfers in mice, that the CD103(pos) ICOS(pos) phenotype represents a LN-specific differentiation stage arrived at by several other Treg-cell subsets. Thus, tissue-specific cues determine the overall potency of the peripheral Treg-cell pool by shaping its subset composition.
Autoimmune polyendocrine syndrome type-1 clinically manifests as the triad of hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis. Mutations in the gene ...that encodes the autoimmune regulator protein, AIRE, have been identified as the cause of the autoimmune polyendocrine syndrome type-1. The loss of immunologic tolerance to tissue-restricted antigens consequent to an absence of AIRE expression in the thymus results in the thymic export of autoreactive T cells that initiate autoimmunity. In this article, we discuss the role of AIRE in autoimmune polyendocrine syndrome type-1 and identify issues that still need to be addressed to fully understand the molecular pathophysiology of this complex syndrome.
The thymus constitutes the primary lymphoid organ responsible for the generation of naive T cells. Its stromal compartment is largely composed of a scaffold of different subsets of epithelial cells ...that provide soluble and membrane-bound molecules essential for thymocyte maturation and selection. With senescence, a steady decline in the thymic output of T cells has been observed. Numeric and qualitative changes in the stromal compartment of the thymus resulting in reduced thymopoietic capacity have been suggested to account for this physiologic process. The precise cellular and molecular mechanisms underlying thymic senescence are, however, only incompletely understood. Here, we demonstrate that TGF-β signaling in thymic epithelial cells exerts a direct influence on the cell’s capacity to support thymopoiesis in the aged mouse as the physiologic process of thymic senescence is mitigated in mice deficient for the expression of TGF-βRII on thymic epithelial cells. Moreover, TGF-β signaling in these stromal cells transiently hinders the early phase of thymic reconstitution after myeloablative conditioning and hematopoietic stem cell transplantation. Hence, inhibition of TGF-β signaling decelerates the process of age-related thymic involution and may hasten the reconstitution of regular thymopoiesis after hematopoietic stem cell transplantation.
The transcription factor FOXN1 is a master regulator of thymic epithelial cell (TEC) development and function. Here, we demonstrate that FOXN1 expression is differentially regulated during ...organogenesis and participates in multimolecular nuclear condensates essential for the factor’s transcriptional activity. FOXN1’s C-terminal sequence regulates the diffusion velocity within these aggregates and modulates the binding to proximal gene regulatory regions. These dynamics are altered in a patient with a mutant FOXN1 that is modified in its C-terminal sequence. This mutant is transcriptionally inactive and acts as a dominant negative factor displacing wild-type FOXN1 from condensates and causing athymia and severe lymphopenia in heterozygotes. Expression of the mutated mouse ortholog selectively impairs mouse TEC differentiation, revealing a gene dose dependency for individual TEC subtypes. We have therefore identified the cause for a primary immunodeficiency disease and determined the mechanism by which this FOXN1 gain-of-function mutant mediates its dominant negative effect.
T‐cell production throughout life depends on efficient colonization and intrathymic expansion of BM‐derived hematopoietic precursors. After irradiation‐induced thymic damage, thymic recovery is ...facilitated by Flt3 ligand (FL), expressed by perivascular fibroblasts surrounding the thymic entry site of Flt3 receptor‐positive progenitor cells. Whether intrathymic FL–Flt3 interactions play a role in steady‐state replenishment of T cells remains unknown. Here, using competitive BM transplantation studies and fetal thymic organ cultures we demonstrated the continued numerical advantage of Flt3+ intrathymic T‐cell precursors. Sub‐kidney capsule thymic transplantation experiments, in which WT and FL−/− thymic lobes were grafted into FL−/− recipients, revealed that FL expression by the thymic microenvironment plays a role in steady‐state thymopoiesis. The deficiency of the most immature thymic T‐cell precursors correlated to upregulation of FL by thymic MTS15+ fibroblasts, suggesting that the number of Flt3+ progenitor cells may regulate the thymic expression of this cytokine. Together, these results show that FL expression by thymic stromal fibroblasts interacting with Flt3+ T‐cell progenitors is important for the physiological maintenance of early T‐cell development.
Background The thymus constitutes the primary lymphoid organ for the majority of T cells. The phosphatidyl-inositol 3 kinase (PI3K) signaling pathway is involved in lymphoid development. Defects in ...single components of this pathway prevent thymocytes from progressing beyond early T cell developmental stages. Protein kinase B (PKB) is the main effector of the PI3K pathway. Methodology/Principal Findings To determine whether PKB mediates PI3K signaling in the thymus, we characterized PKB knockout thymi. Our results reveal a significant thymic hypocellularity in PKBα−/− neonates and an accumulation of early thymocyte subsets in PKBα−/− adult mice. Using thymic grafting and fetal liver cell transfer experiments, the latter finding was specifically attributed to the lack of PKBα within the lymphoid component of the thymus. Microarray analyses show that the absence of PKBα in early thymocyte subsets modifies the expression of genes known to be involved in pre-TCR signaling, in T cell activation, and in the transduction of interferon-mediated signals. Conclusions/Significance This report highlights the specific requirements of PKBα for thymic development and opens up new prospects as to the mechanism downstream of PKBα in early thymocytes.
The thymus in GVHD pathophysiology Krenger, Werner, PhD; Holländer, Georg A., MD
Best practice & research. Clinical haematology,
06/2008, Letnik:
21, Številka:
2
Journal Article
Recenzirano
A favorable outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) depends on the complete reconstitution of the host's immune system. While recovery of peripheral T cells occurs in ...transplant recipients via both thymus-dependent and thymus-independent pathways, the regeneration of a population of phenotypically naive T cells with a broad T-cell receptor (TCR) repertoire relies entirely on the de novo generation of T cells in the thymus. However, preclinical models and clinical studies of allogeneic HSCT have identified the thymus as a target of graft-versus-host disease (GVHD). The present review focuses on recent insight into how GVHD affects thymic function and how this knowledge aides the design of new strategies to improve immune reconstitution following allogeneic HSCT.
Activated lymphocytes and lymphoid-tissue inducer cells express lymphotoxins (LTs), which are essential for the organogenesis and maintenance of lymphoreticular microenvironments. Here we describe ...that T-cell-restricted overexpression of LT induces fulminant thymic involution. This phenotype was prevented by ablation of the LT receptors tumor necrosis factor receptor (TNFR) 1 or LT beta receptor (LTβR), representing two non-redundant pathways. Multiple lines of transgenic Ltαβ and Ltα mice show such a phenotype, which was not observed on overexpression of LTβ alone. Reciprocal bone marrow transfers between LT-overexpressing and receptor-ablated mice show that involution was not due to a T cell-autonomous defect but was triggered by TNFR1 and LTβR signaling to radioresistant stromal cells. Thymic involution was partially prevented by the removal of one allele of LTβR but not of TNFR1, establishing a hierarchy in these signaling events. Infection with the lymphocytic choriomeningitis virus triggered a similar thymic pathology in wt, but not in Tnfr1−/− mice. These mice displayed elevated TNFα in both thymus and plasma, as well as increased LTs on both CD8+ and CD4− CD 8− thymocytes. These findings suggest that enhanced T cell-derived LT expression helps to control the physiological size of the thymic stroma and accelerates its involution via TNFR1/LTβR signaling in pathological conditions and possibly also in normal aging.
T cell development is tightly controlled by thymic stromal cells. Alterations in stromal architecture affect T cell maturation and the development of self-tolerance. The monogenic autoimmune syndrome ...APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy) is characterized by the loss of self-tolerance to multiple organs. Although mutations in the autoimmune regulator (AIRE) gene are responsible for this disease, the function of AIRE is not known. Here we report on the spatial and temporal pattern of murine Aire expression during thymic ontogeny and T cell selection. Early during development, thymic Aire transcription is critically dependent on RelB and occurs in epithelial cells in response to lymphocyte-mediated signals. In adult tissue, Aire expression is confined to the medulla and the corticomedullary junction, where it is modulated by thymocytes undergoing negative selection. Aire may determine thymic stromal organization and with it the induction of self-tolerance.
Monoallelic Expression of the Interleukin-2 Locus Holländer, Georg A.; Zuklys, Saulius; Morel, Corinne ...
Science (American Association for the Advancement of Science),
03/1998, Letnik:
279, Številka:
5359
Journal Article
Recenzirano
The lymphokine interleukin-2 (IL-2) is responsible for autocrine cell cycle progression and regulation of immune responses. Uncontrolled secretion of IL-2 results in adverse reactions ranging from ...anergy, to aberrant T cell activation, to autoimmunity. With the use of fluorescent in situ hybridization and single-cell polymerase chain reaction in cells with different IL-2 alleles, IL-2 expression in mature thymocytes and T cells was found to be tightly controlled by monoallelic expression. Because IL-2 is encoded at a nonimprinted autosomal locus, this result represents an unusual regulatory mode for controlling the precise expression of a single gene.
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