T cell activation-associated epitopes of CD147 in regulation of the T cell response, and their definition by antibody affinity and antigen density

Abstract

CD147 is a broadly expressed cell surface glycoprotein of the Ig superfamily whose expression is up-regulated upon T cell activation. In order to elucidate a possible role of CD147 in T cell biology, we established 15 specific mAb. Seven distinct epitopes were defined by the mAb panel. Most of the mAb bound only to phytohemagglutinin (PHA)-activated but not resting T cells. We demonstrate that this was not because of true expression of activation-dependent neoepitopes but rather due to bivalent binding of the relatively low-affinity mAb (affinity constant KA values between 2.25 x 10(8) and 7 x 10(9) M-1) to the more densely expressed and/or more clustered CD147 molecules on the activated T cells. In contrast, the mAb with higher affinity (KA > 7 x 10(9) M-1) could stably bind in a monovalent fashion even to the relatively low dense CD147 molecules on resting T cells. This model might more generally explain the nature of 'activation epitopes' described previously in other leukocyte surface molecules. Finally, we provide evidence that induction of ordered dimerization of CD147 by a mAb directed to a unique epitope results in strong inhibition of CD3-mediated T cell activation.

High incidence of EMMPRIN expression in human tumors

“…Furthermore, various physiological processes, such as proliferation and differentiation of epithelial cells, [47][48][49] fertilization, 18 differentiation and activation of immune cells, 10,50,51 integrin-mediated adhesion of myocytes of the left heart ventricle to basement membrane components, 52 selective transport processes in endothelial cells to maintain blood-brain-barrier function, 15 erythrocyte maturation 53 or wound healing 54 might also be influenced by an anti-EMMPRIN therapy.…”

“…6 The preparation and specificity of these antibodies have been described in detail elsewhere. 10,24 Sections were counterstained with Mayer's Hemalaun solution (Merck, Darmstadt, Germany). MOPC-21 (Sigma, Deisenhofen, Germany, at 15 lg/ml), an unrelated mouse myeloma immunoglobulin, served as the IgG1 isotype control.…”

“…9 Furthermore, EMMPRIN has been reported to be involved in immune cell activation, 10,11 in processes mediating viral entry into cells, 12 in cell-cell interactions in the developing nervous system, 13 in blood-brain barrier development 14,15 or in cyclophilin function. 16 Moreover, EMM-PRIN knockout mice are often sterile or present with deficiencies in spermatogenesis and fertilization.…”

Caveolin-1 Regulates Matrix Metalloproteinases-1 Induction and CD147/EMMPRIN Cell Surface Clustering

“…Antibodies and Cell Lines-Antibodies to CD147 were rabbit polyclonal antiserum B10 and mAb 8G6 (16,26), and mAb M6/13 and AAA6 (32,33). Anti-caveolin-1 rabbit polyclonal was from BD Transduction Laboratories, San Diego, CA.…”

A phase 2/3 multicenter randomized clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute graft-versus-host disease

“…Upon activation, CD147 is markedly up-regulated on activated lymphocytes. 17 ABX-CBL is capable of inhibiting the in vitro mixed lymphocyte reaction by depleting monocytes and activated lymphocytes via a complement-dependent cytotoxic mechanism. Both activated T cells (CD4 ϩ and CD8 ϩ ) and B cells are depleted by ABX-CBL, while resting lymphocytes are unaffected.…”