{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T07:47:58Z","timestamp":1769759278364,"version":"3.49.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T00:00:00Z","timestamp":1734998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic graft-versus-host disease (cGVHD) manifests with characteristics of autoimmune disease with organs attacked by pathogenic helper T cells. Recent studies have highlighted the role of T cells in cGVHD pathogenesis. Due to limited understanding of underlying mechanisms, preventing cGVHD after allogenic hematopoietic cell transplantation (HCT) has become a major challenge.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Here, we used a representative cGVHD model with the donor C57BL\/6 to recipient BALB\/c combination. Post-HCT, mice were treated with IgG or anti-CD4 monoclonal antibody. The severity of cGVHD was assessed by evaluating symptoms of cGVHD and histopathology examination (H&amp;amp;E) of target organs. Thymus gland damage and defects of the negative selection were assessed by analyzing the CD4<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> double-positive thymocytes, cortical thymic epithelial cells and medullary thymic epithelial cells (mTECs). Immunotolerance of CD8<jats:sup>+<\/jats:sup> T cells was assessed by detecting the expression of CD80, PD-1, GRAIL and IL-7R\u03b1. Long-term cellular and humoral immunity associated with graft-versus-leukemia (GVL) effects were evaluated through detecting the percentage of CD4<jats:sup>+<\/jats:sup> T cells, IgG, IgM and IgA concentrations, and performing tumor challenge experiment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Donor CD8<jats:sup>+<\/jats:sup> T cells caused thymic epithelial cells damage and impaired negative selection in recipients, leading to generation of autoreactive T cells and causing cGVHD. Anti-CD4 mAb treatment promoted immune incompetence of thymus-infiltrating CD8<jats:sup>+<\/jats:sup> T cells, facilitated recovery of CD4<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> thymocytes and regeneration mTECs, and preserved negative-selection, but had no effects on the long-term cellular immunity and humoral immunity, resulting in preservation of GVL effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results indicate that anti-CD4 mAb therapy early post-HCT allows thymus recovery by inducing the immune tolerance of thymus infiltrated CD8<jats:sup>+<\/jats:sup> T cells, thereby alleviating thymic epithelial cells damage, preserving negative selection, and preserving long-term GVL effect at the same 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