{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:52:00Z","timestamp":1792673520817,"version":"4.5.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Naturally derived regulatory T cells (Tregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of naturally derived regulatory T cells has been severely hampered by their scarce availability and nonselectivity. To overcome these limitations, we took alternative approaches to generate Ag-specific induced Tregs (iTregs) and tested their efficacy and selectivity in the prevention of GVHD in preclinical models of bone marrow transplantation. We selected HY as a target Ag because it is a naturally processed, ubiquitously expressed minor histocompatibility Ag (miHAg) with a proven role in GVHD and GVL effect. We generated HY-specific iTregs (HY-iTregs) from resting CD4 T cells derived from TCR transgenic mice, in which CD4 cells specifically recognize HY peptide. We found that HY-iTregs were highly effective in preventing GVHD in male (HY+) but not female (HY\u2212) recipients using MHC II-mismatched, parent\u2192F1, and miHAg-mismatched murine bone marrow transplantation models. Interestingly, the expression of target Ag (HY) on the hematopoietic or nonhematopoietic compartment alone was sufficient for iTregs to prevent GVHD. Furthermore, treatment with HY-iTregs still preserved the GVL effect even against pre-established leukemia. We found that HY-iTregs were more stable in male than in female recipients. Furthermore, HY-iTregs expanded extensively in male but not female recipients, which in turn significantly reduced donor effector T cell expansion, activation, and migration into GVHD target organs, resulting in effective prevention of GVHD. This study demonstrates that iTregs specific for HY miHAgs are highly effective in controlling GVHD in an Ag-dependent manner while sparing the GVL effect.<\/jats:p>","DOI":"10.4049\/jimmunol.1401250","type":"journal-article","created":{"date-parts":[[2015,6,6]],"date-time":"2015-06-06T02:50:19Z","timestamp":1433559019000},"page":"717-725","source":"Crossref","is-referenced-by-count":29,"title":["HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease"],"prefix":"10.1093","volume":"195","author":[{"given":"Jun","family":"Li","sequence":"first","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"},{"name":"Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Heinrichs","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, University of South Florida, Tampa , FL 33620"},{"name":"Department of Microbiology and Immunology, Medical University of South Carolina , Charleston, SC 29425"},{"name":"Division of Hematology\/Oncology, Department of Medicine, Medical University of South Carolina , Charleston, SC 29425"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelley","family":"Haarberg","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"},{"name":"Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenrick","family":"Semple","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"},{"name":"Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anandharaman","family":"Veerapathran","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"},{"name":"Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida , Gainesville, FL 32611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Anasetti","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"},{"name":"Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"},{"name":"Department of Pathology and Cell Biology, University of South Florida, Tampa , FL 33620"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Zhong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"},{"name":"Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612"},{"name":"Department of Microbiology and Immunology, Medical University of South Carolina , Charleston, SC 29425"},{"name":"Division of Hematology\/Oncology, Department of Medicine, Medical University of South Carolina , Charleston, SC 29425"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,7,15]]},"reference":[{"key":"2025030703433527700_r1","doi-asserted-by":"crossref","first-page":"4685","DOI":"10.4049\/jimmunol.179.7.4685","article-title":"Autoantigen-specific TGFbeta-induced Foxp3+ regulatory T cells prevent autoimmunity by inhibiting dendritic cells from activating autoreactive T cells","volume":"179","author":"DiPaolo","year":"2007","journal-title":"J. Immunol."},{"key":"2025030703433527700_r2","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1084\/jem.20040139","article-title":"In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes","volume":"199","author":"Tang","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025030703433527700_r3","doi-asserted-by":"crossref","first-page":"6629","DOI":"10.4049\/jimmunol.0904044","article-title":"TGF-beta-induced myelin peptide-specific regulatory T cells mediate antigen-specific suppression of induction of experimental autoimmune encephalomyelitis","volume":"184","author":"Zhang","year":"2010","journal-title":"J. Immunol."},{"key":"2025030703433527700_r4","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1002\/eji.200526077","article-title":"Antigen-dependent suppression of alloresponses by Foxp3-induced regulatory T cells in transplantation","volume":"35","author":"Albert","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"2025030703433527700_r5","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.bbmt.2010.12.710","article-title":"Efficient and selective prevention of GVHD by antigen-specific induced Tregs via linked-suppression in mice","volume":"17","author":"Semple","year":"2011","journal-title":"Biol. Blood Marrow Transplant."},{"key":"2025030703433527700_r6","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1182\/blood-2003-07-2603","article-title":"Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants","volume":"103","author":"Randolph","year":"2004","journal-title":"Blood"},{"key":"2025030703433527700_r7","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1084\/jem.20031560","article-title":"Minor histocompatibility antigen DBY elicits a coordinated B and T cell response after allogeneic stem cell transplantation","volume":"199","author":"Zorn","year":"2004","journal-title":"J. Exp. 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Immunol."},{"key":"2025030703433527700_r15","doi-asserted-by":"crossref","first-page":"5011-5020","DOI":"10.1182\/blood-2011-03-340315","article-title":"Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and ROR\u03b3t in mice","volume":"118","author":"Yu","year":"2011","journal-title":"Blood"},{"key":"2025030703433527700_r16","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1084\/jem.20030152","article-title":"Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3","volume":"198","author":"Chen","year":"2003","journal-title":"J. Exp. 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Clin. Invest."},{"key":"2025030703433527700_r24","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1038\/sj.gt.3301004","article-title":"Induction of P815 tumor immunity by recombinant Semliki Forest virus expressing the P1A gene","volume":"6","author":"Colmenero","year":"1999","journal-title":"Gene Ther."},{"key":"2025030703433527700_r25","doi-asserted-by":"crossref","first-page":"83ra41","DOI":"10.1126\/scitranslmed.3001809","article-title":"Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity","volume":"3","author":"Hippen","year":"2011","journal-title":"Sci. Transl. 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Transplant."},{"key":"2025030703433527700_r29","doi-asserted-by":"crossref","first-page":"e38","DOI":"10.1371\/journal.pbio.0050038","article-title":"Epigenetic control of the foxp3 locus in regulatory T cells","volume":"5","author":"Floess","year":"2007","journal-title":"PLoS Biol."},{"key":"2025030703433527700_r30","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1182\/blood-2007-06-094656","article-title":"Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype","volume":"110","author":"Tran","year":"2007","journal-title":"Blood"},{"key":"2025030703433527700_r31","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1158\/1078-0432.CCR-10-3347","article-title":"Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease","volume":"17","author":"Beres","year":"2011","journal-title":"Clin. 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