IL-10-Engineered Human CD4+ Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism

Mol Ther. 2017 Oct 4;25(10):2254-2269. doi: 10.1016/j.ymthe.2017.06.029. Epub 2017 Jul 5.


T regulatory cells (Tregs) play a key role in modulating T cell responses. Clinical trials showed that Tregs modulate graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, their ability to mediate anti-leukemic activity (graft-versus-leukemia [GvL]) is largely unknown. Enforced interleukin-10 (IL-10) expression converts human CD4+ T cells into T regulatory type 1 (Tr1)-like (CD4IL-10) cells that suppress effector T cells in vitro and xenoGvHD in humanized mouse models. In the present study, we show that CD4IL-10 cells mediate anti-leukemic effects in vitro and in vivo in a human leukocyte antigen (HLA) class I-dependent but antigen-independent manner. The cytotoxicity mediated by CD4IL-10 cells is granzyme B (GzB) dependent, is specific for CD13+ target cells, and requires CD54 and CD112 expression on primary leukemic target blasts. CD4IL-10 cells adoptively transferred in humanized mouse models directly mediate anti-tumor and anti-leukemic effects. In addition, when co-transferred with peripheral blood mononuclear cells (PBMCs), CD4IL-10 cells contribute to the GvL activity but suppress xenoGvHD mediated by the PBMCs. These findings provide for the first time a strong rationale for CD4IL-10 cell immunotherapy to prevent GvHD and promote GvL in allo-HSCT for myeloid malignancies.

Keywords: gene transfer; immunotherapy; tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes
  • Humans
  • Immunotherapy
  • Interleukin-10 / metabolism*
  • Leukemia, Myeloid / immunology
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / therapy*
  • Leukocytes, Mononuclear / metabolism*
  • Models, Biological
  • T-Lymphocytes, Regulatory / metabolism*


  • Interleukin-10