CD137 (4-1BB) costimulation of CD8+ T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation

Nat Commun. 2021 Dec 15;12(1):7296. doi: 10.1038/s41467-021-27613-w.


CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-κB signaling and provides a more robust induction of cell cycle and DNA damage repair gene expression programs. Here we report that the superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which may provide costimulation either in cis or in trans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / genetics
  • CD3 Complex / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Cytokines / genetics
  • Cytokines / immunology
  • Humans
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Receptor-CD3 Complex, Antigen, T-Cell / genetics
  • Receptor-CD3 Complex, Antigen, T-Cell / immunology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology*


  • CD3 Complex
  • Cytokines
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Tumor Necrosis Factor Receptor Superfamily, Member 9