Involvement of CD70–CD27 interactions in the induction of experimental autoimmune encephalomyelitis
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.
Section snippets
Mice
Female SJL/J mice, 6–10 weeks old, were purchased from SLC (Shizuoka, Japan). All mice were housed in animal care facilities and were used in accordance with the guidelines of the Committee on Animals of Juntendo University School of Medicine.
Monoclonal antibodies and peptides
Rat monoclonal antibody (mAb) against murine CD70 was generated in our laboratory (Oshima et al., 1998). This mAb, named FR-70, specifically reacted with murine CD70 transfectants and prevented anti-CD3-stimulated T cell proliferation costimulated by CD70
Anti-CD70 mAb inhibits the development of active EAE
Immunization of EAE-susceptible female SJL/J mice with PLP139–151 in CFA H37Ra resulted in the development of chronic relapsing EAE. The first neurologic signs appeared on or around day 13 post-immunization in almost all animals. To address the functional role of the CD70–CD27 interaction on the development of EAE, the mice immunized with PLP peptide in CFA H37Ra on day 1 were i.p. administered anti-CD70 mAb daily from day 0 to 3 and then three times a week until day 20 when the first remission
Discussion
In the present study, we showed the critical contribution of CD70–CD27 costimulation to cell-mediated immunity in vivo by demonstrating that the development of active EAE, a prototype of cell-mediated autoimmunity, was markedly inhibited by the administration of anti-CD70 mAb. In contrast, treatment with anti-CD70 mAb did not affect adoptively transferred EAE. This was also confirmed by the result that late treatment with anti-CD70 mAb did not prevent active EAE. In addition, we also
Acknowledgements
We thank Dr. C. Garrison Fathman, Christine M. Seroogy, and Anthony J. Slavin for critical reading of the manuscript and Dr. Yutakelgo for technical assistance. This work was partly supported by grants from the Ministry of Education, Science, Sports and Culture and the Ministry of Health, Japan.
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2017, Current Opinion in VirologyCitation Excerpt :Since CD27 co-stimulation influences the production of pro-inflammatory cytokines, it might contribute to the pathology associated with inflammatory autoimmune diseases [10]. Indeed, SJL/J [56], DBA/1 [57] and RAG−/− [58] mice activated to induce disease in the absence of CD27-stimulation had a reduction (∼4-times) in clinical scores [9,30], suggesting that CD27 co-stimulation might be detrimental during particular autoimmune diseases, and that blocking CD27 co-stimulation may be a feasible option for future autoimmune immunotherapies (Table 4). During chronic viral infections, T-cells become ‘exhausted’ [59].