The relevance of soluble CD137 in the regulation of immune responses and for immunotherapeutic intervention

The expression of the murine T cell Ag 4-1BB, a member of the TNF-R family, is induced by T cell activation. Previously, we and others had shown that signaling through 4-1BB enhanced proliferative T cell responses. To investigate a potential role for the interaction of 4-1BB with its ligand (4-1BBL) in T cell activation, we studied the ability of a soluble chimera of 4-1BB (4-1BBFc) to interfere with proliferative responses and cytokine production in models of activation dependent in intercellular interactions. The potential blocking effect of 4-1BBFc was compared with that of the chimeric molecule CTLA-4Ig, a reagent known to interfere with the interaction of CD28 (and/or CTLA-4) with B7 costimulatory receptors. In this study, we report that 4-1BBFc partially blocked both the activation of unfractionated splenocytes triggered by soluble anti-CD3 (anti-CD3s), and the more physiologically relevant responses to alloantigen. In addition, we show that both chimeric molecules partially blocked proliferative responses and IL-2 secretion by highly purified resting T cells activated with anti-CD3s in the presence of fixed accessory cells that express B7 receptors and 4-1BBL. Furthermore, in this model system, the blocking capacity of 4-1BBFc and CTLA-4Ig appears to correlate with the relative expression of their respective cognate receptors (4-1BBL and B7) on the accessory cell. Simultaneous addition of both blocking reagents produced an additive effect in the model systems studied.

CD137 is a potent co-stimulatory molecule on activated T cells, and its ligand (CD137L) is expressed on antigen presenting cells (APC). Ectopic expression of CD137 has been identified on Hodgkin Reed-Sternberg (HRS) cells, the malignant cells in Hodgkin Lymphoma (HL), and CD137 on HRS cells was found to support growth of HRS cells and escape from immune surveillance. HRS cells are mostly derived from B cells, which poses the question of how B cells acquire ectopic CD137 expression during the transformation process. HL is associated with Epstein-Barr virus (EBV) infection. We show that the EBV latent membrane protein 1 (LMP1) induces expression of CD137 in HRS cell lines. In a HL tissue microarray, 96% of the CD137-positive HL cases stained positive for LMP1. LMP1 utilizes the PI3K-AKT-mTOR pathway for inducing CD137 expression. These findings support the role of EBV in HL pathogenesis.

Increasing evidence shows that costimulatory molecules of the tumor necrosis factor superfamily such as CD40/CD40 ligand and OX40/OX40 ligand have been implicated in atherosclerosis. We investigated whether the expression levels of the tumor necrosis factor superfamily members CD137 in serum and membrane-bound were related to acute coronary syndromes (ACS). Thirty normal controls and 210 patients, including 70 with stable angina (SA), 80 with unstable angina (UA), and 60 with acute myocardial infarction (AMI), were enrolled in our study. The expression of CD137 in peripheral monocytes was analyzed by flow cytometry. Serum soluble CD137 (sCD137) and C-reactive protein levels were measured by commercially available ELISA. The expression of CD137 in peripheral monocytes in patients with UA [14.2+/-3.5 mean fluorescence intensity (MFI)] and AMI (15.1+/-4.4MFI) was significantly higher than those in patients with SA (6.5+/-2.4MFI) and controls (7.1+/-3.5MFI). sCD137 in patients with UA (16.7+/-4.9 ng/ml) and AMI (19.1+/-4.3 ng/ml) were significantly higher than those in patients with SA (3.4+/-1.4 ng/ml) and controls (3.9+/-1. 3 ng/ml) (p<0.001). C-reactive protein level in serum in patients with UA (13.8+/-3.3 ng/ml) and AMI (15.5+/-4.7 ng/ml) were also higher than those in patients with SA (1.4+/-0.4 ng/ml) and controls (1.3+/-0.3ng/ml). It was interesting that percutaneous transluminal coronary angioplasty (PTCA) induced a marked rise in sCD137 levels in SA patients, while CD137 expression in peripheral monocytes showed no difference between SA patients with PTCA before and after. A positive correlation was found between sCD137 and serum C-reactive protein levels (r=0.681; p<0.0001). Patients with ACS showed increased soluble and membrane-bound CD137 expression. sCD137 level showed a significantly positive correlation with CRP level in patients with ACS. The relation between sCD137 and ACS needs further researches. Copyright 2009 Elsevier B.V. All rights reserved.