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Transl. Med."],"published-print":{"date-parts":[[2026,10,21]]},"abstract":"<jats:p>Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T cell\u2013mediated complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free\/relapse-free survival for posttransplant cyclophosphamide (PT-Cy)\u2013based GVHD prophylaxis versus tacrolimus\/methotrexate (Tac\/MTX), but the T cell biology underpinning these outcomes remains unknown. To determine this, 324 patients were coenrolled onto BMT CTN 1801 to investigate the distinct T cell immune reconstitution pathways of these regimens, including extensive evaluation of T cell receptor (TCR) repertoire, via sequencing of 2359 longitudinal samples and 180,432,350 T cells. Multimodal T cell analysis revealed that PT-Cy was associated with pan\u2013T cell deletion followed by delayed T cell expansion from a smaller founder population compared with Tac\/MTX. This created a T cell diversity bottleneck, leading to reduced TCR repertoire diversity for 2 years posttransplant. Reduced TCR diversity, more common in patients receiving PT-Cy, was linked to protection against chronic GVHD when patients were analyzed without regard to study arm. Leveraging donor- and host-specific TCR clonal analysis, we determined that PT-Cy\u2013mediated T cell depletion also depleted pathogen-specific TCRs, rendering PT-Cy patients more likely to lack detectable graft-derived pathogen-specific TCRs early after transplant, which was associated with an increased risk of severe infection. This study reveals how distinct immunosuppression strategies uniquely remodel T cell immunity and shape divergent transplant outcomes.<\/jats:p>","DOI":"10.1126\/scitranslmed.aef7406","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:58:57Z","timestamp":1792605537000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2754-3537","authenticated-orcid":true,"given":"Susan","family":"DeWolf","sequence":"first","affiliation":[{"name":"Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven 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