Modulation of the Immune Response Through 4-1BB
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MODULATION OF THE IMMUNE RESPONSE THROUGH 4-1BB Gabriel Sica and Lieping Chen Department of Immunology, Mayo Clinic 200 First Street, Southwest Rochester, Minnesota 55905, USA
1. INTRODUCTION 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). 41BBL 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).
2. ROLE OF 4-1BB AND 4-1BBL IN THE IMMUNE RESPONSE T cells require two signals for activation, signal one is provided by the interaction of the T cell receptor (TCR) with the appropriate MHC/peptide and signal two is Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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provided by costimulatory pathways such as the well known B7-CD28 pathway. Interaction of naive T cell TCR with MHC/peptide complex without a costimulatory signal can lead to T cell unresponsiveness (Chen, 1998). Naive T cells are most efficiently activated and induced to proliferate by interacting with professional antigen presenting cells (APC) such as B cells, macrophages, and dendritic cells. Professional APCs are well suited to activate naive T cells because of their ability to supply both signals for T cell activation and the presence of multiple molecules involved in costimulation (e.g. B7-1, B7-2, 41BBL, OX40L). Many of the costimulatory molecules are upregulated after activation/ma
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