Involvement of CD70–CD27 interactions in the induction of experimental autoimmune encephalomyelitis

Abstract

CD70/CD27 are cell surface molecules belonging to the TNF/TNF-receptor families. Ligation of CD27 by its ligand CD70 is thought to be important in T cell activation and T cell–B cell interaction. However, the in vivo function of these molecules during the establishment of cell-mediated immunity remains unclear. In this study, we examined the contribution of CD70–CD27 interactions to cell-mediated immunity by investigating the effect of anti-CD70 mAb on the development of experimental autoimmune encephalomyelitis (EAE). Treatment of SJL/J mice with anti-CD70 mAb prevented EAE induced by immunization with PLP_139–151. The preventive effect of anti-CD70 mAb was not due to the inhibition of T cell priming and antibody production from B cells, or immune deviation. However, TNF-α production was suppressed by treatment with anti-CD70 mAb, indicating that the ameliorating effect of anti-CD70 mAb appeared, at least in part, to be mediated by the inhibition of TNF-α production. These results indicate that the CD70–CD27 interaction plays a pivotal role in the development of cell-mediated autoimmune disease.

Introduction

Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated inflammatory disease of the central nervous system (CNS) widely used as an animal model for multiple sclerosis (MS). Immunohistological analysis of mononuclear cell infiltrates in the CNS revealed that macrophages as well as T cells constitute the major recruited cell population (Hohlfelt et al., 1995, Miller and Karpus, 1994). The pathogenesis of EAE and MS, though not fully understood, is believed to be mediated by activated CD4⁺ T cells of the T helper type 1 (Th1) phenotype (Steinman, 1996).

It has been well established that efficient activation of T cells requires not only the T cell receptor (TCR)-mediated signals upon antigen recognition, but also costimulatory signals provided by the contact with antigen-presenting cells (APC) (Mueller et al., 1989, Schwartz, 1992). Among the several costimulatory molecules characterized, interaction of CD28 on T cells with B7 (CD80 and CD86) on APC appears to be of primary importance (June et al., 1994, Lenschow et al., 1996). While the CD28–B7 interaction constitutes a predominant pathway of T cell costimulation, some intact T cell responses in CD28-deficient mice have suggested the presence of alternative pathways (Ding and Shevach, 1996, Shahinian et al., 1993). Several groups have reported other membrane-bound receptor–ligand pairs to be costimulators of T cell activation. In particular, members of the TNF receptor family and their respective ligands have recently been shown to share the ability to enhance or costimulate the process of T cell activation (DeBenedette et al., 1997, Grewal and Flavell, 1996a, Grewal and Flavell, 1996b, Hurtade et al., 1995, Lynch et al., 1995, Smith et al., 1994). It is becoming apparent, however, that members of the TNF ligand family play unique and critical roles in both the development of the immune system and in immune responses to specific pathogens. One such receptor–ligand pair, CD27 and CD70, have been shown to provide a second signal for T cell proliferation (Goodwin et al., 1993, Agematsu et al., 1994, Hintzen et al., 1994, Hintzen et al., 1995, Kobata et al., 1994, Oshima et al., 1998). While CD27 is constitutively expressed on T cells, expression of CD70 in vivo is rather restricted, so that it was found on chronically activated T cells, in particular conditions such as autoimmune reactions (Brugnoni et al., 1997). These data suggest a possible role of CD70–CD27 interactions in the pathogenesis of immune dysregulation. Recent in vitro results suggest that CD70–CD27 interactions play critical roles not only in T cell activation but also in T cell-dependent Ig production by B cells, suggesting that the CD70–CD27 interactions may constitute a component of the T cell–B cell interaction seen after activation with antigen or mitogen (Agematsu et al., 1997, Jacquot et al., 1997, Kobata et al., 1995). However, the contribution of these molecules in autoimmune diseases, especially in cell-mediated autoimmunity such as EAE, remains unclear.

To investigate the role of CD70–CD27 costimulation in cell-mediated autoimmune diseases, we studied the contribution of the CD70–CD27 costimulatory pathway to the pathogenesis of EAE. In vivo administration of anti-CD70 mAb markedly prevented the development of EAE. In vitro experiments revealed that anti-CD70 mAb inhibited antigen-induced TNF-α production without affecting T cell priming, Ig production or Th1/Th2 balance. These results indicate that CD70–CD27 interactions play an important role in the induction of cell-mediated autoimmune diseases.