Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies

Nat Med. 2017 Dec;23(12):1416-1423. doi: 10.1038/nm.4444. Epub 2017 Nov 13.


Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor β-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1+ and TRBC2+ compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1+, but not TRBC2+, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.

Publication types

  • Validation Study

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Jurkat Cells
  • K562 Cells
  • Leukemia, T-Cell / immunology
  • Leukemia, T-Cell / therapy*
  • Male
  • Mice
  • Molecular Targeted Therapy / methods
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • T-Lymphocytes / immunology


  • Antineoplastic Agents, Immunological
  • Receptors, Antigen, T-Cell, alpha-beta