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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 resting T cells. Here we report the immunological characterization of mice lacking 4-1BBL and of mice lacking both 4-1BBL and CD28. 4-1BBL-/- mice mount neutralizing IgM and IgG responses to vesicular stomatitis virus that are indistinguishable from those of wild-type mice. 4-1BBL-/- mice show unimpaired CTL responses to lymphocytic choriomeningitis virus (LCMV) and exhibit normal skin allograft rejection but have a weaker CTL response to influenza virus than wild-type mice. 4-1BBL-/-CD28-/- mice retain the CTL response to LCMV, respond poorly to influenza virus, and exhibit a delay in skin 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 vitro secondary response of CD28+ T cells to influenza virus peptides. TCR-transgenic CD28-/- LCMV glycoprotein-specific T cells are insensitive to the 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. These results further substantiate the idea that different immune responses vary in their dependence on costimulation and suggest a role for 4-1BBL in augmenting suboptimal CTL responses in vivo.


Journal article


Journal of immunology (Baltimore, Md. : 1950)

Publication Date





4833 - 4841


Department of Immunology, University of Toronto, Ontario, Canada.


T-Lymphocytes, Cytotoxic, Tumor Cells, Cultured, Animals, Mice, Inbred A, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Mice, Knockout, Mice, Lymphocytic choriomeningitis virus, Influenza A virus, Tumor Necrosis Factor-alpha, Antibodies, Viral, Ligands, Skin Transplantation, Gene Targeting, Cytotoxicity, Immunologic, Graft Rejection, Female, Male, 4-1BB Ligand, Vesicular stomatitis Indiana virus, CD28 Antigens