Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor

Nat Biotechnol. 2002 Jan;20(1):70-5. doi: 10.1038/nbt0102-70.


Artificial receptors provide a promising approach to target T lymphocytes to tumor antigens. However, the receptors described thus far produce either an activation or a co-stimulatory signal alone, thus limiting the spectrum of functions accomplished by the genetically modified cells. Here we show that human primary T lymphocytes expressing fusion receptors directed to prostate-specific membrane antigen (PSMA) and containing combined T-cell receptor-zeta (TCRzeta), and CD28 signaling elements, effectively lyse tumor cells expressing PSMA. When stimulated by cell-surface PSMA, retrovirally transduced lymphocytes undergo robust proliferation, expanding by more than 2 logs in three weeks, and produce large amounts of interleukin-2 (IL-2). Importantly, the amplified cell populations retain their antigen-specific cytolytic activity. These data demonstrate that fusion receptors containing both TCR and CD28 signaling moieties are potent molecules able to redirect and amplify human T-cell responses. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of tumor cells that fail to express major histocompatibility complex antigens and co-stimulatory molecules.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CD28 Antigens / chemistry*
  • CD28 Antigens / metabolism*
  • Cell Division
  • Cells, Cultured
  • Flow Cytometry
  • Gene Transfer Techniques
  • Humans
  • Interleukin-2 / biosynthesis
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Protein Binding
  • Receptors, Antigen, T-Cell / chemistry*
  • Receptors, Antigen, T-Cell / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Retroviridae / genetics
  • T-Lymphocytes / cytology*
  • T-Lymphocytes, Cytotoxic / cytology*
  • Time Factors
  • Transduction, Genetic


  • CD28 Antigens
  • Interleukin-2
  • Membrane Proteins
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • antigen T cell receptor, zeta chain