Soluble CD137 and Autoimmune Diseases
CD137 has been detected in both membrane-bound mCD137 and soluble forms sCD137 . Expression level of soluble forms of CD137 does not always correlate with that of mCD137, since they are generated by alternative splicing Setareh et al., 1995 instead of a proteolytic product of mCD137. Two splice variants of sCD137 has been identified Michel et al., 1998 . Expression of both membrane-bound and soluble isoforms is activation-dependent Schwarz et al., 1996 , while the production of sCD137 seems to...
CD137 and Memory T Cell Tm Response
The generation and maintenance of immunological memory is the ultimate goal of vaccination. Upon exposure to antigen, antigen-specific T cells proliferate enormously and develop into effector T cells capable of immediate effector functions. Following a successful immune response, the effector T cell population undergoes significant contraction. Only small fraction about 5-10 of antigen-specific T-cell population survives and is maintained indefinitely. In comparison with extensive knowledge on...
Effects of CD137 Engagement on CD8 T Cells in vitro
There is ample evidence that CD137 signal plays an important role in costim-ulation of T cell activation in the presence of T cell receptor TCR signal in vitro. Cross-linking of CD137 by anti-CD137 antibody resulted in an enhancement of purified splenic T cell proliferation compared to that stimulated by anti-CD3 alone Pollok et al., 1993 . Similarly, CD137 engagement by immobilized CD137L fusion protein or CD137L transfectants augmented the T cell proliferation and cytokine production Goodwin...
Effects of CD137 Engagement on CD8 T Cells in vivo
Ligation of CD137 on naive T cells by CD137L or CD137 antibody in the absence of TCR signal does not induce detectable responses DeBenedette et al., 1997 Pollok et al., 1993 . Because naive T cells do not express detectable CD137 Cannons etal., 2001 Pollok et al., 1995 , it is thus possible that TCR is required for upregulation of CD137 on T cell surface. Studies of CD137 expression in vitro indicate that CD137 is expressed 24 h after activation with peak expression at 48-72 h Cannons etal.,...
CD137 Expression and T Cell Costimulation
CD137 is an activation inducible member of the TNFR superfamily and is found on activated thymocytes, T cells Kwon et al., 1994 Pollok et al., 1993 Schwarz et al., 1995 , and NK cells Melero et al., 1998b . It has recently been found on granulocytes Heinisch et al., 2000 , eosinophils Heinisch et al., 2001 , macrophages Kienzle and von Kempis, 2000 Langstein et al., 1998 , DC Futagawa et al., 2002 Pauly et al., 2002 Summers et al., 2001 Wilcox et al., 2002 , and within the intra-tumor...
Dendritic Cells
Dendritic cells DCs are among the most potent antigen-presenting cells for the priming of T cell responses, thus contributing to adaptive immunity. In addition, DCs also participate in innate immunity. First, DCs express abundant molecules which are responsible for the activation of NK cells Degli-Esposti and Smyth, 2005 . Second, DCs can release an array of cytokines, upon activation, which are important in the regulation of immune responses, including innate immunity Steinman et al., 2005 ....
Discovery Alternative Names and Structure of CD137
CD137 was first identified in screens for receptors on mouse concanavalin A-activated helper and cytotoxic T cell lines Kwon and Weissman, 1989 . CD137 also called 4-1BB was originally named induced by lymphocyte activation ILA in humans, and 4-1BB in the mouse Pollok et al., 1993 Schwarz et al., 1993 . It is a 30-kD glycoprotein and exists both as a monomer and a 55-kD dimer on the T cell surface. The entire gene spans approximately 13 kb of mouse chromosome 4.
CD137 Ligand Activities on Monocytes and Macrophages
CD137 ligand is expressed constitutively on peripheral monocytes and mono-cyte macrophage cell lines Table 3.2 . The signal through CD137 ligand activates monocytes and the CD137 lig-and signal alone is sufficient for activation. When CD137 ligand is crosslinked by recombinant CD137 protein or an anti-CD137 ligand antibody, it induces adherence of monocytes within a few hours. The adherent monocytes change their shape over the course of a week and adopt the three basic macrophage morphologies,...
Yuwen Zhu and Lieping Chen
CD4 and CD8 T cells express high level of CD137 on the cell surface upon activation. A well-documented function of CD137 is its costimulatory effect on both CD4 and CD8 T cell growth and differentiation in vitro. In vivo experiments, however, reveal a far more complex effect of CD137 signaling on T cell-mediated immunity. Administration of CD137 agonistic mAb delivers a potent stimulatory signal and leads to CD8 T cell-mediated viral clearance and tumor regression in various models. In sharp...
Robert S Mittler Liguo Niu Becker Hewes and Juergen Foell
CD137 4-1BB , a member of the tumor necrosis factor receptor TNFR superfamily is an activation-inducible type I transmembrane protein receptor expressed on activated T cells, Natural Killer cells NK , macrophages M , and dendritic cells DC . Its ligand, 4-1BB-L, is a member of the tumor necrosis factor TNF superfamily a type II transmembrane protein that is expressed on antigen presenting cells APC . Ligand-induced trimerization of CD137 activates multiple signaling pathways in T cells that...
CD137 Signal Transduction
T lymphocytes have critical roles in clearing cells expressing foreign antigens. The proliferation of T cells and their differentiation into effector and memory cells confers T cell-mediated adaptive immunity Abbas et al., 1997 . To undertake these antigen-specific functions, T cells require two signals ligation of the T cell receptor TCR by the MHC peptide complex on the antigen presenting cell APC , and cross-linking of co-stimulatory receptors on the T cell with corresponding ligands on the...
MacrophagesMonocyte
Macrophages are phagocytic cells that accumulate in inflammatory sites. In addition to phagocytosis and subsequent antigen processing and presentation, macrophages also express cell surface molecules and secrete a wide variety of different cytokines, including IL-1,IL-6, IL-8, IL-12, and TNF-a, upon exposure to pathogens and cancer cells. Therefore, macrophages could have local and systemic effects and serve not only to amplify the innate immune response, but also to trigger adaptive immunity....
Contributors
Aplicada y Cl nica Universitaria Universidad de Navarra Pamplona, Spain and Oncology Emory University School of Medicine 954 Gatewood Road Atlanta, GA 30329 LSU Eye Center, Louisiana State University Health Sciences Center New Orleans, LA USA LSU Eye Center, Louisiana State University Health Sciences Center New Orleans, LA USA Aplicada y Cl nica Universitaria Universidad de Navarra Pamplona, Spain Department of Physiology, National University of Singapore 2 Medical Drive, MD 9 Singapore 117597...
CD137CD137L in Health and Disease
The importance of CD137-CD137L interactions has been underscored in several experimental systems Vinay and Kwon, 1998 . Expression of CD137 CD137L has been reported in various clinical disorders. Yamada-Okabe et al. 2003 demonstrated that thyroid hormone induced CD137 expression along with caspases. Also, expression of CD137 was detected in the inflammatory tissue in Crohn's disease Maerten et al., 2004 . Interestingly, soluble forms of CD137 and CD137L were found in serum samples collected...
CD137 Ligand Activities on T Cells
Expression of CD137 ligand protein could either not be detected on primary T cells, or only at low levels. But CD137 ligand is present on human and murine T cell lines Table 3.2 . It may be that CD137 ligand is expressed on primary T cells at such low levels that detection by commonly used detection methods such as flow cytometry is difficult. T cell lines may acquire stronger CD137 ligand expression during the transformation process. The activities of CD137 ligand on T cells stand in contrast...
CD137L Structure and Expression
CD137L is a 34 kD type II membrane glycoprotein with a carboxy-terminal extracellular domain and its gene is on chromosome 17 in the mouse Goodwin et al., 1993 . Although human CD137 ligand huCD137L is present in both T and B cells of the peripheral blood, the ligand is preferentially expressed in primary B cells and B cell lines. Daudi, a B cell lymphoma, is one of the B cell lines with the highest number of ligand molecules Zhou et al., 1995 . Scatchard analysis gave a kd of 1.4 x 10-9 M and...
Overview
Co-stimulation, an integral component of immune regulation, is required for progressive T cell activation. T cell activation without co-stimulation induces anergy in which subsequent stimulation inhibits T cell responsiveness Schwartz, 1990 . Since the description of the two-signal model for T cell activation by Bretscher and Cohn 1970 , understanding of the activation requirements of T cells has progressed rapidly and attained further prominence with the emergence of the CD28-B7 pathway....
The CD137 Gene
Accession numbers human AL009183, AY438976 and mouse U02567 The CD137 cDNA was initially isolated from activated murine T cells by a modified differential screening procedure Kwon and Weissman, 1989 . Its deduced amino acid sequence and its transcript expression profile indicated that it was an inducible T cell surface molecule Kwon and Weissman, 1989 Pollok etal., 1993 . CD137 was categorized as an early activation gene because the protein synthesis inhibitor, cyclohexamide, blocked formation...