Establishment of Central Tolerance in Steady State and Haplo-HSCT (IMAGE)
Caption
Early thymic progenitor (ETP) cells, derived from hematopoietic stem cells in the bone marrow, enter the thymus at the cortical-medullary junction (CMJ), retaining multipotent differentiation potential. T-cells develop from these progenitors through a well-defined process. Double-negative (DN) thymocytes undergo TCR gene rearrangement during β-selection, processing into double-positive (DP) thymocytes, where they undergo the selection process to acquire MHC restriction and establish self-tolerance. Positive selection ensures that thymocytes with non-functional TCRs undergo death by neglect, while negative selection eliminates thymocytes with excessively high-affinity TCR-pMHC interactions or stronger responses to self-antigens through clonal deletion. Antigen-presenting cells (APCs) play critical roles in these processes. Cortical thymic epithelial cells (cTECs) primarily mediate positive selection, whereas negative selection is more complex. Extrathymic APCs, including B cells, macrophages, migratory dendritic cells (DCs), and plasmacytoid DCs (pDCs), transport peripheral tissue-restricted antigens (TRAs) to the thymus and directly interact with single-positive (SP) thymocytes to promote central tolerance. Migratory DCs and macrophages may facilitate negative selection by acquiring antigens from medullary thymic epithelial cells (mTECs) via antigen transfer or phagocytosis. Intrathymic APCs, including resident conventional DCs (cDCs) and mTECs, promote negative selection. mTEC either directly present TRAs or transfer antigens to resident DCs, which then trigger clonal deletion of thymocytes with high-affinity self-pMHC interactions. Following negative selection, mature SP T-cells express CCR7 and S1PR1, enabling their migration into the peripheral circulation. In haplo-HSCT, donor-derived HSPCs undergo thymic selection, shifting recipient antigens from non-self to self. During this process, donor-derived hematopoietic APCs present exogenous donor MHC molecules, while recipient-derived intrathymic APCs present recipient MHC molecules. However, the impact of this complex antigen presentation on T-cell regeneration, particularly in central tolerance, including negative selection and Treg differentiation, remains largely unexplored.
Credit
Professor Xiao-Jun Huang, Peking University People’s Hospital, Beijing, China Image source link: https://link.springer.com/article/10.1007/s44466-025-00008-y/figures/1
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