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

Itziar Otano, Arantza Azpilikueta, Javier Glez-Vaz, Maite Alvarez, José Medina-Echeverz, Ivan Cortés-Domínguez, Carlos Ortiz-de-Solorzano, Peter Ellmark, Sara Fritzell, Gabriela Hernandez-Hoyos, Michelle Hase Nelson, María Carmen Ochoa, Elixabet Bolaños, Doina Cuculescu, Patricia Jaúregui, Sandra Sanchez-Gregorio, Iñaki Etxeberria, María E. Rodriguez-Ruiz, Miguel F. Sanmamed, Álvaro TeijeiraPedro Berraondo, Ignacio Melero

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number7296
JournalNature Communications
Issue number1
Publication statusPublished - 2021 Dec 1

Subject classification (UKÄ)

  • Cell and Molecular Biology


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