4-1BB (CD 137) is a 30kDa type I (N terminus extracellular) membrane glycoprotein receptor that belongs to the tumor necrosis factor receptor (TNFR) superfamily which also include molecules such as CD27, CD40, Fas (CD95), OX40, and TNFR I/II. Members of the TNFR superfamily are important molecules in the activation, enhancement, and/or downregulation of immune responses, especially cellular immune responses, and are characterized by the presence 2–4 cysteine rich extracellular modules. 4-1BB was originally cloned from stimulated cytolytic T lymphocyte and helper T lymphocyte clone cDNA and its expression is highly limited to lymphoid organs (Kwon et al., 1989). Surface expression of 4-1BB can be detected by flow cytometry on activated CD8+ and CD4+ T cells, activated thymocytes, intraepithelial lymphocytes, activated natural killer (NK) cells, and eosinophils (Goodwin et al., 1993; Melero et al., 1998b; Pinto et al., 1997; Zhou et al., 1994). 4-1BB is not detected on the surface of resting T cells or resting/activated B cells (DeBenedette et al., 1995; Garni-Wagner et al., 1996; Pollok et al., 1995). 4-1BB mRNA is up-regulated approximately 3 hours after T cell activation and can be detected on the surface as early as 24 hours after T cell activation (Garni-Wagner et al., 1996; Pollok et al., 1993). The natural ligand for 4-lBB (4-lBBL) is a type II (C terminus extracellular) membrane glycoprotein of 34kDa that is a member of the tumor necrosis factor (TNF) superfamily which includes molecules such as OX40 ligand, CD27 ligand, CD40 ligand (CD 154), and lymphotoxin(Alderson et al., 1994; Goodwin et al., 1993). 4-1BBL can be detected on the surface of activated T cells, macrophages, monocytes, dendritic cells, B cells, and some murine B lymphomas (Goodwin et al., 1993).