{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T07:17:26Z","timestamp":1775114246244,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2006,2,1]],"date-time":"2006-02-01T00:00:00Z","timestamp":1138752000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2006,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Interleukin\u20101 receptor antagonist (IL\u20101Ra)\u2013deficient 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\u20101Ra\/CD28\u2013double\u2010deficient mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We crossed IL\u20101Ra\u2013deficient mice with CD28\u2013deficient mice and observed the incidence and severity of arthritis. To investigate functions of IL\u20101Ra\/CD28\u2013double\u2010deficient T cells, cells were stimulated with CD3 monoclonal antibody or allogeneic antigen\u2010presenting cells (APCs) and their proliferative responses and levels of cytokine production were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Disease severity was lower in IL\u20101Ra\/CD28\u2013double\u2010deficient mice than in mice that were deficient only in IL\u20101Ra, although incidence of arthritis was not affected by the presence or absence of CD28. When pathogenic IL\u20101Ra\u2013KO T cells were transferred into nude mice, severe arthritis developed. Even though T cells from double\u2010deficient mice showed the same diminished proliferative capacity as was seen in T cells from CD28\u2013single\u2010deficient animals, nude mice into which double\u2010deficient T cells were transferred never developed arthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings indicate that IL\u20101Ra\/CD28\u2013double\u2010deficient T cells can be activated by IL\u20101Ra\u2013deficient 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.21769","type":"journal-article","created":{"date-parts":[[2006,2,1]],"date-time":"2006-02-01T17:16:25Z","timestamp":1138814185000},"page":"473-481","source":"Crossref","is-referenced-by-count":10,"title":["CD28\u2010dependent differentiation into the effector\/memory phenotype is essential 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