CD28-independent, TRAF2-dependent costimulation of resting T cells by 4- 1BB ligand

Katina Saoulli, Soo Young Lee, Jennifer L. Cannons, Wen Chen Yeh, Angela Santana, Marni D. Goldstein, Naveen Bangia, Mark A. DeBenedette, Tak W. Mak, Yongwon Choi, Tania H. Watts

Research output: Contribution to journalArticlepeer-review

277 Scopus citations


4-1BB ligand (4-1BBL) is a member of the tumor necrosis factor (TNF) family expressed on activated antigen-presenting cells. Its receptor, 4-1BB, is a member of the TNF receptor family expressed on activated CD4 and CD8 T cells. We have produced a soluble form of 4-1BBL using the baculovirus expression system. When coimmobilized on plastic with anti-CD3, soluble 4- 1BBL induces interleukin (IL)-2 production by resting CD28+ or CD28- T cells, indicating that 4-1BBL can function independently of other cell surface molecules, including CD28, in costimulation of resting T cell activation. At low concentrations of anti-CD3, 4-1BBL is inferior to anti- CD28 in T cell activation. However, when 4-1BB ligand is provided together with strong TCR signals, then 4-1BBL and anti-CD28 are equally potent in stimulation of IL-2 production by resting T cells. We find that TNF receptor- associated factor (TRAF)1 or TRAF2 associate with a glutathione S- transferase-4-1BB cytoplasmic domain fusion protein in vitro. In T cells, we find that association of TRAF1 and TRAF2 with 4-1BB requires 4-1BB cross- linking. In support of a functional role for TRAF2 in 4-1BB signaling, we find that resting T cells isolated from TRAF2-deficient mice or from mice expressing a dominant negative form of TRAF2 fail to augment IL-2 production in response to soluble 4-1BBL. Thus 4-1BB, via the TRAF2 molecule, can provide CD28-independent costimulatory signals to resting T cells.

Original languageEnglish
Pages (from-to)1849-1862
Number of pages14
JournalJournal of Experimental Medicine
Issue number11
StatePublished - 1 Jun 1998


  • 4-1BB
  • Costimulation
  • Signaling
  • T cells
  • TRAF2


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