Chimeric antigen receptor-induced BCL11B suppression propagates NK-like cell development

J Clin Invest. 2019 Dec 2;129(12):5108-5122. doi: 10.1172/JCI126350.


The transcription factor B cell CLL/lymphoma 11B (BCL11B) is indispensable for T lineage development of lymphoid progenitors. Here, we show that chimeric antigen receptor (CAR) expression during early phases of ex vivo generation of lymphoid progenitors suppressed BCL11B, leading to suppression of T cell-associated gene expression and acquisition of NK cell-like properties. Upon adoptive transfer into hematopoietic stem cell transplant recipients, CAR-expressing lymphoid progenitors differentiated into CAR-induced killer (CARiK) cells that mediated potent antigen-directed antileukemic activity even across MHC barriers. CD28 and active immunoreceptor tyrosine-based activation motifs were critical for a functional CARiK phenotype. These results give important insights into differentiation of murine and human lymphoid progenitors driven by synthetic CAR transgene expression and encourage further evaluation of ex vivo-generated CARiK cells for targeted immunotherapy.

Keywords: Immunology; Immunotherapy; Leukemias; T cell development; Transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / metabolism
  • CD28 Antigens / metabolism*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Separation
  • Cytotoxicity, Immunologic
  • Flow Cytometry
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Immunotherapy
  • Immunotherapy, Adoptive
  • Killer Cells, Natural / cytology*
  • Lymphocytes / cytology*
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Protein Engineering
  • Receptors, Chimeric Antigen / metabolism*
  • Repressor Proteins / metabolism*
  • Stem Cells / cytology
  • T-Lymphocytes / cytology*
  • Transgenes
  • Tumor Suppressor Proteins / metabolism*


  • Antigens, CD19
  • BCL11B protein, human
  • Bcl11b protein, mouse
  • CD19 antigen, mouse
  • CD19 molecule, human
  • CD28 Antigens
  • Receptors, Chimeric Antigen
  • Repressor Proteins
  • Tumor Suppressor Proteins