Indirect presentation in the thymus limits naive and regulatory T‐cell differentiation by promoting deletion of self‐reactive thymocytes

• Published in: Immunology Vol. 154; no. 3; pp. 522 - 532
• Main Authors: Yap, Jin Yan, Wirasinha, Rushika C., Chan, Anna, Howard, Debbie R., Goodnow, Christopher C., Daley, Stephen R.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2018; John Wiley and Sons Inc
• Subjects: Animals; Antigen presentation; Antigen Presentation - immunology; Antigen-presenting cells; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Antigens; Autoantigens; Autoantigens - immunology; Biomarkers; Bone marrow; Cell Differentiation; central tolerance; Clonal deletion; Clonal Selection, Antigen-Mediated - immunology; Developmental stages; Differentiation (biology); Epithelial cells; Foxp3 protein; Gene Expression; Immune Tolerance; Immunological tolerance; Immunophenotyping; Immunoregulation; indirect presentation; Insulin; Lymphocytes; Lymphocytes T; Lysozyme; Major histocompatibility complex; Medulla oblongata; Mice; Mice, Knockout; Original; Phenotype; regulatory T cells; Signal transduction; T cell receptors; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Thymocytes; Thymocytes - cytology; Thymocytes - immunology; Thymocytes - metabolism; Thymus; Thymus Gland - cytology; Thymus Gland - immunology; Thyroglobulin; T‐cell deletion; T‐cell tolerance; regulatory T cells; T-cell tolerance; central tolerance; indirect presentation; T-cell deletion
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12904

Summary Acquisition of T‐cell central tolerance involves distinct pathways of self‐antigen presentation to thymocytes. One pathway termed indirect presentation requires a self‐antigen transfer step from thymic epithelial cells (TECs) to bone marrow‐derived cells before the self‐antigen is presented to thymocytes. The role of indirect presentation in central tolerance is context‐dependent, potentially due to variation in self‐antigen expression, processing and presentation in the thymus. Here, we report experiments in mice in which TECs expressed a membrane‐bound transgenic self‐antigen, hen egg lysozyme (HEL), from either the insulin (insHEL) or thyroglobulin (thyroHEL) promoter. Intrathymic HEL expression was less abundant and more confined to the medulla in insHEL mice compared with thyroHEL mice. When indirect presentation was impaired by generating mice lacking MHC class II expression in bone marrow‐derived antigen‐presenting cells, insHEL‐mediated thymocyte deletion was abolished, whereas thyroHEL‐mediated deletion occurred at a later stage of thymocyte development and Foxp3+ regulatory T‐cell differentiation increased. Indirect presentation increased the strength of T‐cell receptor signalling that both self‐antigens induced in thymocytes, as assessed by Helios expression. Hence, indirect presentation limits the differentiation of naive and regulatory T cells by promoting deletion of self‐reactive thymocytes. Acquisition of T‐cell central tolerance involves distinct pathways of self‐antigen presentation to thymocytes. One pathway termed indirect presentation requires intercellular self‐antigen transfer before self‐antigen presentation. Yap et al. provide evidence that the requirement for indirect presentation in T‐cell central tolerance is greater when intrathymic self‐antigen expression is lower and more restricted to the thymic medulla.