title: HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease.
abstract: 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(-)) recipients using MHC II-mismatched, parent→F1, 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.
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology and Cell Biology, University of South Florida, Tampa, FL 33620; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Heinrichs
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Kelley
authors.initials: K
authors.lastname: Haarberg
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Kenrick
authors.initials: K
authors.lastname: Semple
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Anandharaman
authors.initials: A
authors.lastname: Veerapathran
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32611.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Pathology and Cell Biology, University of South Florida, Tampa, FL 33620;
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and yux@musc.edu.
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect; D006182:H-Y Antigen / Q000235:genetics / Q000276:immunology*; D006650:Histocompatibility Testing; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012737:Sex Factors; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D006182:H-Y Antigen