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.
Original language | English (US) |
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Article number | e1146842 |
Journal | OncoImmunology |
Volume | 5 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2 2016 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2016 Taylor & Francis Group, LLC.
Keywords
- Cytolytic function
- Foxp3
- Treg therapy
- graft-versus-host disease
- graft-versus-leukemia
- regulatory T cells