Regular ArticleThymic microenvironments, 3-D versus 2-D?☆
Abstract
Lympho-stromal interactions in the thymus crucially de- termine the fate of developing T cells. Epithelial cells, inter- digitating reticular cells, macrophages and fibroblasts all play a role in the shaping of the T cell repertoire. Recently published evidence shows that lympho-stromal interaction acts bi-directional. Developing T cell themselves, at different stages of differentiation, control the microarchitecture of thymic microenvironments, a phenomenon designated as `crosstalk'. This paper reviews experiments showing that developing T cells crosstalk to different thymic epithelial cells in a stepwise fashion. In this way, correctly organized thymic microenvironments guarantee normal thymopoiesis.
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Laminin-2 immobilized on a 3D fibrous structure impacts cortical thymic epithelial cells behaviour and their interaction with thymocytes
2022, International Journal of Biological MacromoleculesThe tri-dimensionality of the thymic extracellular matrix (ECM) supports the crosstalk between thymocytes and thymic epithelial cells (TECs). The thymic ECM component laminin-2 is involved in the regulation of thymocytes and their interaction with cortical TECs (cTECs). Most in vitro studies use planar surfaces to study the interaction between ECM components and thymic cells. Herein, we developed a novel biofunctionalized culture system by immobilizing laminin-2 at the surface of porous and fibrous electrospun meshes. We aimed to study the interaction of cTECs with thymocytes in the presence of laminin-2 presented through this system. The results indicated that the presence of laminin-2, not its density, has a positive effect on the cell viability and proliferation of cTECs. qPCR results demonstrated that laminin-2 density influenced the expression of cTECs genes. An increased percentage of adherent CD4−CD8− thymocytes and a decreased percentage of CD4+CD8+ thymocytes were evident in higher laminin-2 concentrations. Higher concentrations decreased the expression of Il7 and Ccl25 in cTECs after thymocyte adhesion. Altogether, these results indicate that the interaction of thymocytes with the thymic cortical compartment is affected by laminin-2 density and supports the need for immobilized ECM proteins in porous and fibrous substrates for the study of thymus biology.
Successful organoid-mediated generation of iPSC-derived CAR-T cells
2022, Cell Stem CellArtificial thymic organoids (ATOs) allow the selective differentiation of chimeric antigen receptor (CAR)-transduced human iPSCs into CAR-T cells. In this issue of Cell Stem Cell, Wang et al. now use ATOs to produce human CD19+ CAR-T cells that mimic conventional CAR-T cells and effectively control the progression of human CD19+ leukemia in an animal model.
Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells
2020, Journal of Allergy and Clinical ImmunologyPatients with T-cell immunodeficiencies are generally treated with allogeneic hematopoietic stem cell transplantation, but alternatives are needed for patients without matched donors. An innovative intrathymic gene therapy approach that directly targets the thymus might improve outcomes.
We sought to determine the efficacy of intrathymic adeno-associated virus (AAV) serotypes to transduce thymocyte subsets and correct the T-cell immunodeficiency in a zeta-associated protein of 70 kDa (ZAP-70)–deficient murine model.
AAV serotypes were injected intrathymically into wild-type mice, and gene transfer efficiency was monitored. ZAP-70−/− mice were intrathymically injected with an AAV8 vector harboring the ZAP70 gene. Thymus structure, immunophenotyping, T-cell receptor clonotypes, T-cell function, immune responses to transgenes and autoantibodies, vector copy number, and integration were evaluated.
AAV8, AAV9, and AAV10 serotypes all transduced thymocyte subsets after in situ gene transfer, with transduction of up to 5% of cells. Intrathymic injection of an AAV8–ZAP-70 vector into ZAP-70−/− mice resulted in a rapid thymocyte differentiation associated with the development of a thymic medulla. Strikingly, medullary thymic epithelial cells expressing the autoimmune regulator were detected within 10 days of gene transfer, correlating with the presence of functional effector and regulatory T-cell subsets with diverse T-cell receptor clonotypes in the periphery. Although thymocyte reconstitution was transient, gene-corrected peripheral T cells harboring approximately 1 AAV genome per cell persisted for more than 40 weeks, and AAV vector integration was detected.
Intrathymic AAV-transduced progenitors promote a rapid restoration of the thymic architecture, with a single wave of thymopoiesis generating long-term peripheral T-cell function.
The interbranchial lymphoid tissue likely contributes to immune tolerance and defense in the gills of Atlantic salmon
2017, Developmental and Comparative ImmunologyCentral and peripheral immune tolerance is together with defense mechanisms a hallmark of all lymphoid tissues. In fish, such tolerance is especially important in the gills, where the intimate contact between gill tissue and the aqueous environment would otherwise lead to continual immune stimulation by innocuous antigens. In this paper, we focus on the expression of genes associated with immune regulation by the interbranchial lymphoid tissue (ILT) in an attempt to understand its role in maintaining immune homeostasis. Both healthy and virus-challenged fish were investigated, and transcript levels were examined from laser-dissected ILT, gills, head kidney and intestine. Lack of Aire expression in the ILT excluded its involvement in central tolerance and any possibility of its being an analogue to the thymus. On the other hand, the ILT appears to participate in peripheral immune tolerance due to its relatively high expression of forkhead box protein 3 (Foxp3) and other genes associated with regulatory T cells (Tregs) and immune suppression.
Single-cell insights into transcriptomic diversity in immunity
2017, Current Opinion in Systems BiologyOur body is composed of a diverse set of cells that together perform numerous functions in a highly coordinated manner, allowing a timely response to external cues and to inter-cellular signals. Emerging single-cell technologies enable investigation of these intricate processes at an unprecedented level.
Here, we discuss recent work on cellular differentiation and heterogeneity, and describe novel experimental and computational tools that enable this research. As an example of cellular differentiation, we focus on T cell development in response to diverse infections and in immune pathologies. We then describe how single-cell studies have contributed to our understanding of transcriptional variability in innate immune response, and how this variability might be important in achieving a balanced immune response.
Future single-cell studies will likely include spatial analyses and lineage tracing strategies, holding great potential to further our understanding of cell behaviour in steady-state and pathological conditions.
Development of Thymic Epithelial Cells
2016, Encyclopedia of ImmunobiologyThe thymus is the primary lymphoid organ in which the T cell repertoire is generated. The complex cellularity of this organ is uniquely designed to facilitate T cell development: defects in thymus development or function can cause immunodeficiencies ranging from the absence of T cell–mediated immunity to broad-spectrum autoimmune disease. Peak thymus size and output occurs early in life, after which the thymus undergoes a natural process of involution. This results in the progressive loss of functional thymus tissue and correspondingly in decreased production of new naïve T cells with age – contributing to the diminished capacity of the aged immune system to adequately respond to new antigenic challenge. Age-related thymic involutions, together with the thymic involutions associated with cytotoxic therapies (e.g., radio- or chemotherapy), have raised interest in development of clinically useful protocols for boosting thymus function in vivo, by reactivating or protecting the endogenous thymus or via thymus transplantation. Improvements in this area are likely to depend on an intimate understanding of the mechanisms regulating development and maintenance of the thymus, and in particular of its stromal components. We here review current understanding of these mechanisms, focusing specifically on the epithelial component of the thymic stroma since this highly specialized lineage directs thymus development and is required critically to mediate many of the organ's specialist functions.
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