title: CD28-dependent differentiation into the effector/memory phenotype is essential for induction of arthritis in interleukin-1 receptor antagonist-deficient mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Tokyo University of Science, Chiba, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Kotani
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hirata
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ogawa
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Habiro
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ishida
authors.forename: Seiichi
authors.initials: S
authors.lastname: Tanuma
authors.forename: Reiko
authors.initials: R
authors.lastname: Horai
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Abe
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D016207:Cytokines; D007156:Immunologic Memory / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D007596:Joints / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D010641:Phenotype; D012795:Sialoglycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins