Li Jun, Heinrichs Jessica, Haarberg Kelley, Semple Kenrick, Veerapathran Anandharaman, Liu Chen, Anasetti Claudio, Yu Xue-Zhong
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; 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.
J Immunol. 2015 Jul 15;195(2):717-25. doi: 10.4049/jimmunol.1401250. Epub 2015 Jun 5.
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.
天然来源的调节性T细胞（Tregs）可能预防移植物抗宿主病（GVHD），同时保留移植物抗白血病（GVL）活性。然而，天然来源的调节性T细胞的临床应用因难以获得且缺乏选择性而受到严重阻碍。为克服这些限制，我们采用替代方法生成抗原特异性诱导调节性T细胞（iTregs），并在骨髓移植的临床前模型中测试其预防GVHD的疗效和选择性。我们选择HY作为靶抗原，因为它是一种天然加工、广泛表达的次要组织相容性抗原（miHAg），在GVHD和GVL效应中已证实有作用。我们从TCR转基因小鼠来源的静息CD4 T细胞中生成HY特异性iTregs（HY-iTregs），其中CD4细胞特异性识别HY肽。我们发现，使用MHC II不匹配、亲代→F1和miHAg不匹配的小鼠骨髓移植模型，HY-iTregs在预防雄性（HY(+)）而非雌性（HY(-)）受体的GVHD方面非常有效。有趣的是，仅造血或非造血区室上靶抗原（HY）的表达就足以使iTregs预防GVHD。此外，用HY-iTregs治疗甚至对已建立的白血病仍保留GVL效应。我们发现HY-iTregs在雄性受体中比在雌性受体中更稳定。此外，HY-iTregs在雄性而非雌性受体中广泛扩增，这反过来又显著减少供体效应T细胞的扩增、激活和向GVHD靶器官的迁移，从而有效预防GVHD。这项研究表明，针对HY miHAgs的iTregs以抗原依赖的方式在控制GVHD方面非常有效，同时不影响GVL效应。
