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

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.
Mesh Terms:
Animals, Antibodies, Antigens, CD, Antigens, CD137, Antigens, CD28, Cell Line, Genetic Vectors, Interleukin-2, Ligands, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Nucleopolyhedrovirus, Proteins, Receptors, Nerve Growth Factor, Receptors, Tumor Necrosis Factor, T-Lymphocytes, TNF Receptor-Associated Factor 1, TNF Receptor-Associated Factor 2
J. Exp. Med.
Date: Jun. 01, 1998
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