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J. Exp. Med.,
Volume 187, Number 11, June 1, 1998 1849-1862
By
From the * Department of Immunology, the 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 Department of Medical Biophysics, and Amgen Institute,
University of Toronto, Toronto, Ontario M5S 1A8, Canada; and the § Howard Hughes Medical
Institute and The Rockefeller University, New York 10021
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.
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