Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease

Hong Zheng, Catherine Matte-Martone, Hongmei Li, Britt E. Anderson, Srividhya Venketesan, Sheng Tan Hung, Dhanpat Jain, Jennifer McNiff, Warren D. Shlomchik

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

Abstract

Much of the efficacy of allogeneic hematopoietic stem cell transplantation (alloSCT) in curing hematologic malignancies is due to a graft-versus-leukemia (GVL) effect mediated by donor T cells that recognize recipient alloantigens on leukemic cells. Donor T cells are also important for reconstituting immunity in the recipient. Unfortunately, donor T cells can attack nonmalignant host tissues and cause graft-versus-host disease (GVHD). We previously reported that donor CD4+ effector memory T cells (TEMs) do not cause GVHD but transfer functional T-cell memory. In the present work, we demonstrate in an MHC-mismatched model that CD4+ TEMs (unprimed to recipient antigens) mediate GVL against clinically relevant mouse models of chronic phase and blast crisis chronic myelogenous leukemia, without causing GVHD. By creating gene-deficient leukemias and using perforin-deficient T cells, we demonstrate that direct cytolytic function is essential for T EM-mediated GVL, but that GVL is retained when killing via FasL, TNF-α, TRAIL, and perforin is individually impaired. However, T EM-mediated GVL was diminished when both FasL and perforin pathways were blocked. Taken together, our studies identify TEMs as a clinically applicable cell therapy for promoting GVL and immune reconstitution, particularly in MHC-mismatched haploidentical alloSCTs in which T cell-depleted allografts are commonly used to minimize GVHD.

Original languageEnglish (US)
Pages (from-to)2476-2484
Number of pages9
JournalBlood
Volume111
Issue number4
DOIs
StatePublished - Feb 15 2008

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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