CD28‐dependent differentiation into the effector/memory phenotype is essential for induction of arthritis in interleukin‐1 receptor antagonist–deficient mice

• Published in: Arthritis and rheumatism 2006-02, Vol.54 (2), p.473-481
• Main Authors: Kotani, Motoko, Hirata, Kazuya, Ogawa, Shuhei, Habiro, Katsuyoshi, Ishida, Yasuo, Tanuma, Seiichi, Horai, Reiko, Iwakura, Yoichiro, Kishimoto, Hidehiro, Abe, Ryo
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - genetics; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Biological and medical sciences; CD28 Antigens - genetics; CD28 Antigens - metabolism; Cell Differentiation; Cell Lineage; Cell Proliferation; Cytokines; Diseases of the osteoarticular system; Immunologic Memory - immunology; Interleukin 1 Receptor Antagonist Protein; Joints - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Nude; Miscellaneous. Osteoarticular involvement in other diseases; Phenotype; Sialoglycoproteins - deficiency; Sialoglycoproteins - genetics; Sialoglycoproteins - immunology; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.21769

Objective Interleukin‐1 receptor antagonist (IL‐1Ra)–deficient mice on a BALB/c background spontaneously develop a chronic inflammatory polyarthropathy closely resembling that of rheumatoid arthritis in humans. To elucidate the role of CD28 costimulatory signals in the development of this disease, we studied IL‐1Ra/CD28–double‐deficient mice. Methods We crossed IL‐1Ra–deficient mice with CD28–deficient mice and observed the incidence and severity of arthritis. To investigate functions of IL‐1Ra/CD28–double‐deficient T cells, cells were stimulated with CD3 monoclonal antibody or allogeneic antigen‐presenting cells (APCs) and their proliferative responses and levels of cytokine production were measured. Results Disease severity was lower in IL‐1Ra/CD28–double‐deficient mice than in mice that were deficient only in IL‐1Ra, although incidence of arthritis was not affected by the presence or absence of CD28. When pathogenic IL‐1Ra–KO T cells were transferred into nude mice, severe arthritis developed. Even though T cells from double‐deficient mice showed the same diminished proliferative capacity as was seen in T cells from CD28–single‐deficient animals, nude mice into which double‐deficient T cells were transferred never developed arthritis. Conclusion These findings indicate that IL‐1Ra/CD28–double‐deficient T cells can be activated by IL‐1Ra–deficient activated APCs, resulting in induction of arthritis; however, these T cells did not induce the disease under normal conditions, because they did not differentiate into effector/memory phenotype.