CD8+ Tregs promote GVHD prevention and overcome the impaired GVL effect mediated by CD4+ Tregs in mice

Jessica Heinrichs, Jun Li, Hung Nguyen, Yongxia Wu, David Bastian, Anusara Daethanasanmak, M. Hanief Sofi, Steven Schutt, Chen Liu, Junfei Jin, Brian Betts, Claudio Anasetti, Xue Zhong Yu

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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 languageEnglish (US)
Article numbere1146842
JournalOncoImmunology
Volume5
Issue number6
DOIs
StatePublished - Jun 2 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology

Keywords

  • Cytolytic function
  • Foxp3
  • Treg therapy
  • graft-versus-host disease
  • graft-versus-leukemia
  • regulatory T cells

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