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Moslecular and biological characterization of human 4‐1BB and its ligands

4‐1BB was originally described as a cDNA expressed by activated murine T cells and subsequently demonstrated to encode a member of the tumor necrosis factor receptor family of integral membrane proteins. Recently, we identified and cloned a murine ligand for 4‐1BB (mu4‐1BB‐L) and demonstrated it to be a member of an emerging family of ligands with structural homology to tumor necrosis factor. To characterize further the role of 4‐1BB in the immune response we undertook to clone the human homologue of 4‐1BB‐L. However, attempts to isolate a cDNA encoding the human 4‐1BB‐L by cross‐hybridization with the murine cDNA were unsuccessful. Therefore we first utilized cross‐species hybridization to isolate a cDNA encoding human 4‐1BB (hu4‐1BB). A fusion protein consisting of the extracellular portion of hu4‐1BB coupled to the Fc region of human immunoglobulin G1 (hu4‐1BB.Fc) was then used to identify and clone a gene for human 4‐1BB‐L from an activated CD4+ T cell clone using a direct expression cloning strategy. Human 4‐1BB‐L shows 36% amino acid identity with its murine counterpart and maps to chromosome 19p13.3. Scatchard analysis demonstrated high‐affinity binding of hu4‐1BB.Fc to either native or recombinant human 4‐1BB‐L. Both monoclonal antibody to hu4‐1BB and cells transfected with hu4‐1BB‐L induced a strong proliferative response in mitogen co‐stimulated primary T cells. In contrast, ligation of 4‐1BB on T cell clones enhanced activation‐induced cell death when triggered by engagement of the TCR/xsCD3 complex.