title: Depletion of host CCR7(+) dendritic cells prevented donor T cell tissue tropism in anti-CD3-conditioned recipients.
abstract: We reported previously that anti-CD3 mAb treatment before hematopoietic cell transplantation (HCT) prevented graft-versus-host disease (GVHD) and preserved graft-versus-leukemia (GVL) effects in mice. These effects were associated with downregulated donor T cell expression of tissue-specific homing and chemokine receptors, marked reduction of donor T cell migration into GVHD target tissues, and deletion of CD103(+) dendritic cells (DCs) in mesenteric lymph nodes (MLN). MLN CD103(+) DCs and peripheral lymph node (PLN) DCs include CCR7(+) and CCR7(-) subsets, but the role of these DC subsets in regulating donor T cell expression of homing and chemokine receptors remain unclear. Here, we show that recipient CCR7(+), but not CCR7(-), DCs in MLN induced donor T cell expression of gut-specific homing and chemokine receptors in a retinoid acid-dependent manner. CCR7 regulated activated DC migration from tissue to draining lymph node, but it was not required for the ability of DCs to induce donor T cell expression of tissue-specific homing and chemokine receptors. Finally, anti-CD3 treatment depleted CCR7(+) but not CCR7(-) DCs by inducing sequential expansion and apoptosis of CCR7(+) DCs in MLN and PLN. Apoptosis of CCR7(+) DCs was associated with DC upregulation of Fas expression and natural killer cell but not T, B, or dendritic cell upregulation of FasL expression in the lymph nodes. These results suggest that depletion of CCR7(+) host-type DCs, with subsequent inhibition of donor T cell migration into GVHD target tissues, can be an effective approach in prevention of acute GVHD and preservation of GVL effects.
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, California.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Racine
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, California.
authors.forename: Heather F
authors.initials: HF
authors.lastname: Johnston
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California; Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California; Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
authors.forename: Nainong
authors.initials: N
authors.lastname: Li
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, California.
authors.forename: Kaniel
authors.initials: K
authors.lastname: Cassady
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California.
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California.
authors.forename: Ruishu
authors.initials: R
authors.lastname: Deng
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, California.
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.affiliation: Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, California. Electronic address: dzeng@coh.org.
authors.forename: Defu
authors.initials: D
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054400:Receptors, CCR7 / Q000276:immunology*; D019707:Receptors, Chemokine / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D018523:Tropism / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D019707:Receptors, Chemokine
keywords: Anti-CD3; CCR7; Dendritic cell; Tissue tropism; Transplantation