Activation, Immune Polarization, and Graft-versus-Leukemia Activity of Donor T-cells are Regulated by Specific Subsets of Donor Bone Marrow Antigen-Presenting Cells in Allogeneic Hematopoietic Stem Cell Transplantation

• Type of Material: Article
• Authors: Jian-Ming Li, Emory University; Lauren T. Southerland, Duke University; Ying Lu, Emory University; Kataryna A. Darlak, Emory University; Cynthia R Giver, Emory University; Douglas W. McMillin, Harvard University; Wayne A.C. Harris, Emory University; David L Jaye, Emory University; Edmund K. Waller, Emory University
• Language: English
• Date: 2009-12-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 by The American Association of Immunologists, Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://www.jimmunol.org/content/183/12/7799
• Title of Journal or Parent Work: Journal of Immunological Methods
• ISSN: 0022-1759
• Volume: 183
• Issue: 12
• Start Page: 7799
• End Page: 7809
• Grant/Funding Information: This work was supported by National Institute of Health Grants R01 CA-74364-03 (to E.K.W.) and NHLBI P01Hl086773 (to C.D.H. and E.K.W.) and an Amy Strelzer Manasevit fellowship sponsored by the National Marrow Donor Program and the SuperGen Corporation and a research fund from When Everyone Survives Foundation, Inc. (J.-M.L.).
• Keywords: Antigen presenting cells; Graft versus Host Disease; Dendritic Cells; Tumor Immunity; T-cells; Cell Activity
• Research Categories: Health Sciences, Immunology

Abstract

We investigated the roles of specific subsets of donor APCs purified from bone marrow in donor T cell activation and graft-vs-leukemia (GvL) activity in murine models of hemopoietic stem cell transplantation. Lineage−CD11c+ APC precursors were separated from donor bone marrow based on expression of CD11b. Transplanting lineage−CD11c+CD11b− APC (CD11b− APC) in combination with c-kit+Sca-1+lineage− hemopoietic stem cells (HSC) and congenic donor T cells led to increased donor CD4+ and CD8+ T cell proliferation and higher donor T cell chimerism than with transplanting grafts containing HSC, T cells, and lineage−CD11c+CD11b+ APCs (CD11b+ APC), or grafts containing only HSC and T cells. Transplanting CD11b− APCs induced Th1/type 1 cytotoxic T lymphocyte donor T cell immune polarization and enhanced GvL activity of donor T cells without increased graft-vs-host disease in both MHC- and minor histocompatibility Ag-mismatched murine hemopoietic stem cell transplantation models, whereas CD11b+ APCs led to Th2/type 2 cytotoxic T lymphocyte donor T cell immune polarization. Donor CD11b− APCs were plasmacytoid dendritic cell progenitors (>90% CD317; PDCA-1+) and up-regulated CD80, CD86, and IL-12 during alloantigen presentation, whereas CD11b+ APCs expressed Gr-1 and up-regulated expression of programmed death ligands-1 and 2 after activation. These results are the first to show that manipulation of the content of donor APCs in allogeneic HSC grafts can regulate donor T cell immunity and enhance GvL without increasing graft-vs-host disease activity.