Single-cell analysis of human thymus and peripheral blood unveils the dynamics of T-cell development and aging.
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ABSTRACT:
PROVIDER: PRJNA970218 | ENA |
REPOSITORIES: ENA
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Project description:Age-related thymic involution is the hallmark of immune aging, leading to susceptibility to cancers and emerging pathogens such as SARS-Cov2 in the elderly. However, the precise mechanisms underlying the thymic involution and the effect on compromised peripheral T-cell function is unknown. Here by scRNA-seq and TCR-seq, we captured and analyzed cells in the thymus and peripheral blood from the young and elderly. Collectively, our data constitute the first detailed single-cell analysis of ageing-related human thymic involution and T-cell homeostasis in peripheral, providing the insights into human immune aging and potential strategies to rejuvenate the involuted thymus and compromised T-cell immunity.
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Project description:The thymus is a primary lymphoid organ generating self-restricted and self-tolerant naïve T-cells. Early in life the thymus starts to involute, resulting in decreased naïve T-cell output which may be more self-reactive, leading to an increased prevalence of autoimmunity. A decrease in the transcription factor FOXN1 is an early event in thymic involution. Using the Foxn1lacz model, we studied how premature thymic involution affects the thymic microenvironment, thymocytes, and peripheral T cell immunity. We found that early thymic involution led to aged-like thymic epithelial cells that resulted in aged-like thymocyte phenotypes, with a significant decrease in CD4+ single-positive T-cells. We also observed severe lymphopenia in Foxn1lacz mice caused by the premature decrease in T-cell production, resulting in a peripheral T-cell phenotype similar to de novo aged peripheral T-cells. Moreover, following T cell receptor stimulation, Foxn1lacz peripheral T cells had reduced IL-2 secretion and strong initial IFN-g responses, resembling aged wild-type peripheral T-cell responses. Lastly, influenza response in Foxn1lacz had a reduction in some aspects of T cell responses to influenza infection, similar to thymectomized mice. Our study shows an independent and direct impact of premature thymic involution on both thymopoiesis and peripheral immune niches likely contributing to immunosenescence and inflammaging as observed in the elderly population.
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Project description:BACKGOUND & AIMS: The role of thymic epithelial cells (TECs) in elimination of self-reactive T cells through presentation of self-antigens is well-established. However, it remains unclear whether TECs can effectively clear hepatocellular carcinoma (HCC)-reactive T cells by presenting HCC-associated antigens. METHODS: HCC nodules and thymuses were harvested from spontaneous and in situ transplanted tumors. Differentially expressed proteins or genes in the aforementioned tissues were determined using liquid chromatograph mass spectrometer (LC-MS) and mRNA transcriptomic sequencing (mRNA-seq). Cell death in histological tissue sections was detected and quantified through the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) technique. Specific protein expression and immune phenotype were evaluated by multiplex immunofluorescence staining and flow cytometry. RESULTS: In comparison to normal thymuses, there is a significant increase in CD8+ T cell death within the thymuses of HCC model mice. Notably, a substantial portion of these dead cells are peripheral activated T cells homing to the thymus. Mechanistically, TECs did not express tumor-associated antigens by themselves, instead, they captured antigens from HCC cells for antigen presentation. Thymus-homing tumor antigen-specific T cells-initiated activation-induced T cell death (AICD) when they recognized the same antigen presented by TECs. Thymectomy suppressed HCC tumor by redistributing CD8+ T cells into the tumor focus. Importantly, instead of thymectomy, adenosine monophosphate activated protein kinase (AMPK) activator and C-C chemokine receptor type 7 (CCR7) antagonist dramatically decreased immune escape while effectively restrained HCC through curtailing the thymus homing of peripheral activated CD8+ T cells. CONCLUSION: Our findings suggest that HCC deceives thymus into recalling and killing peripheral activated CD8+ T cells. Pharmacological blocking thymus homing of CD8+ T cells via AMPK activation and CCR7 antagonism would be an attractive and promising strategy for HCC prevention and treatment.
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Project description:The peptides repertoire presented to CD8+ T cells by major histocompatibility complex (MHC) class I molecules, referred to as the MHC I-associated peptidome (MIP), regulates all critical events that occur during the lifetime of CD8+ T cells. The MIP presented by thymic antigen presenting cells (APCs) is crucial for shaping CD8+ T cell repertoire and self-tolerance, while the MIP presented by peripheral tissues and organs is not only involved in maintaining periphery CD8+ T cell survival and homeostasis, but also mediates immune surveillance and autoimmune responses of CD8+ T cells under pathological conditions. Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by the destruction pancreatic β cells, mediated primarily by autoreactive CD8+ T cells. Non-obese diabetic (NOD) mouse is one of important animal models of spontaneous autoimmune diabetes that shares several key features with human T1D. Here, we deeply analyzed the MIP derived from the primary tissues of thymus and pancreas in NOD mice using targeted database searches of mass spectrometry data. We demonstrated that the thymus MIP source proteins accommodated only a small portion of the transcriptome of thymus epithelial cells, and partially shared with the MIP source proteins derived from NOD mice pancreas and β cell line. The global view of the MHC I-associated self-peptides repertoire in the thymus and pancreas of NOD mice may serve as a biological reference to identify potential autoantigens targeted by autoreactive CD8+ T cells in T1D.
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