Analysis of 4-1BB ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T cell response to influenza virus

4-1BB ligand (4-1BBL) is a member of the TNF family expressed on activated APC. 4-1BBL binds to 4-1BB (CD137) on activated CD4 and CD8 T cells and in conjunction with strong signals through the TCR provides a CD28-independent costimulatory signal leading to high level IL-2 production by primary rest ing T cells. Here we report the immunological characterization of mice lack ing 4-1BBL and of mice lacking both 4-1BBL and CD28. J-1BBL(-/-) mice mount neutralizing IgM and IgG responses to vesicular stomatitis virus that are indistinguishable from those of wild-type mice, 4-1BBL(-/-) mice show unimp aired CTL responses to lymphocytic choriomeningitis virus (LCMV) and exhibi t normal skin allograft rejection but have a weaker CTL response to influen za virus than wild-type mice, 4-1BBL(-/-)CD28(-/-) mice retain the CTL resp onse to LCMV, respond poorly to influenza: virus, and exhibit a delay in sk in allograft rejection, In agreement with these in vivo results, allogeneic CTL responses of CD28(-/-) but not CD28(+/+) T cells to 4-1BBL-expressing APC are substantially inhibited by soluble 4-1BB receptor as is the in vitr o secondary response of CD28(+) T cells to influenza virus peptides, TCR-tr ansgenic CD28(-/-) LCMV glycoprotein-specific T cells are insensitive to th e presence of 4-1BBL when a wild-type peptide is used, but the response to a weak agonist peptide is greatly augmented by the presence of 4-1BBL, Thes e results further substantiate the idea that different immune responses var y in their dependence on costimulation and suggest a role for 4-1BBL in aug menting suboptimal CTL responses in vivo.