image: 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
The ability to distinguish "self" from "non-self" of the immune system, primarily governed by Human Leukocyte Antigens (HLA), raises the central challenge in allogeneic transplantation. “Mismatches historically led to high rates of graft-versus-host disease (GVHD),” the authors note, “However, protocols like the "Beijing Protocol" (G-CSF/ATG-based) and post-transplant cyclophosphamide (PTCy) have successfully bridged this gap.” These approaches have reduced GVHD rates to around 30% in haplo-HSCT, achieving a comparable survival to the HLA-matched HSCT.
Critically, a significant proportion of patients in both haploidentical and matched transplants can eventually discontinue immunosuppressive therapy, indicating that donor immune cells can be "re-educated" to accept the recipient's body as "self." “This shift highlights the process of immune homeostasis remodeling, with thymus-dependent central tolerance playing a key role”, the authors pointed out.
Published in Immunity & Inflammation on December 4, 2025, the review argues that haplo-HSCT serves as an ideal natural model to study this restoration. In haplo-HSCT, donor-derived hematopoietic stem and progenitor cells (HSPCs) undergo thymic selection, shifting recipient antigens from non-self to self. And the donor-derived T-cells can be reconstituted through both peripheral and central pathways.
These mechanisms uncovered provide evidence for developing novel strategies for inducing tolerance in organ transplantation, countering immunosenescence, and repairing that immune system after radio/chemotherapy. “Future directions may involve combined strategies focusing on thymic repair, central tolerance restoration, and non-HLA stratified treatments, to further improve outcomes,” concluded the authors.
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Reference
DOI: 10.1007/s44466-025-00008-y
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Authors
Xiao‑Jun Huang from Peking University
Prof. Xiao‑Jun Huang is an Academician of the Chinese Academy of Engineering. He serves as the director of Peking University Institute of Hematology and the director of the National Clinical Research Center for Hematologic Diseases. He established the world's first ex vivo T-cell-depleted haploidentical hematopoietic stem cell transplantation system-known as the “Beijing Protocol.” He has received numerous awards, including the Ho Leung Ho Lee Foundation Prize for Scientific and Technological Progress, the Guanghua Engineering Science and Technology Award, the Global Distinguished Service Award, and the International Contribution Award. His research focuses on malignant hematologic diseases and hematopoietic stem cell transplantation.
Huidong Guo from Peking University
Dr. Huidong Guo is an associate research fellow in the Institute of Hematology, Peking University People's Hospital. Her research focuses on transplant immunity.
Funding information
This work was supported by the National Natural Science Foundation of China (Grant Numbers 82293630 and 82300243), the Beijing Natural Science Foundation (Grant Number 7252142), and the Beijing Municipal Health Commission project (BRWEP2024W134080115).
Method of Research
Systematic review
Subject of Research
Not applicable
Article Title
HLA haploidentical HSCT: From immune imbalance to a platform for immune homeostasis restoration
Article Publication Date
4-Dec-2025
COI Statement
The corresponding author, Xiao-Jun Huang, is a member of the Editorial Board of Immunity & Inflammation. However, he was not involved in the peer-review or decision-making process for this manuscript. The authors declare no other competing interests.