title: CD8(+) Tregs promote GVHD prevention and overcome the impaired GVL effect mediated by CD4(+) Tregs in mice.
abstract: Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (Allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemia (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4(+) or CD8(+) T cells and tested their ability to suppress GVH and maintain GVL responses. We utilized major mismatched and haploidentical murine models of HCT with host-derived lymphoma or leukemia cell lines to evaluate GVH and GVL responses simultaneously. Alloreactive CD4(+) iTregs were effective in preventing GVHD, but abrogated the GVL effect against aggressive leukemia. Alloreactive CD8(+) iTregs moderately attenuated GVHD while sparing the GVL effect. Hence, we reasoned that using a combination of CD4(+) and CD8(+) iTregs could achieve the optimal goal of Allo-HCT. Indeed, the combinational therapy was superior to CD4(+) or CD8(+) iTreg singular therapy in GVHD control; importantly, the combinational therapy maintained GVL responses. Cellular analysis uncovered potent suppression of both CD4(+) and CD8(+) effector T cells by the combinational therapy that resulted in effective prevention of GVHD, which could not be achieved by either singular therapy. Gene expression profiles revealed alloreactive CD8(+) iTregs possess elevated expression of multiple cytolytic molecules compared to CD4(+) iTregs, which likely contributes to GVL preservation. Our study uncovers unique differences between alloreactive CD4(+) and CD8(+) iTregs that can be harnessed to create an optimal iTreg therapy for GVHD prevention with maintained GVL responses.
authors.affiliation: Department of Pathology and Cell biology, University of South Florida, Tampa, FL, USA; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Heinrichs
authors.affiliation: Department of Hematology, the Third Xiangya Hospital of Central South University , Changsha, Hunan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina , Charleston, SC, USA.
authors.forename: Hung
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina , Charleston, SC, USA.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina , Charleston, SC, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bastian
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina , Charleston, SC, USA.
authors.forename: Anusara
authors.initials: A
authors.lastname: Daethanasanmak
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina , Charleston, SC, USA.
authors.forename: M-Hanief
authors.initials: MH
authors.lastname: Sofi
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina , Charleston, SC, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Schutt
authors.affiliation: Pathology, Immunology and Laboratory Medicine, University of Florida , Gainesville, FL, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China.
authors.forename: Junfei
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pathology and Cell biology, University of South Florida , Tampa, FL, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Betts
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center , Tampa, FL, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
keywords: Cytolytic function; Foxp3; Treg therapy; graft-versus-host disease; graft-versus-leukemia; regulatory T cells