title: Induction of tumor regression by administration of B7-Ig fusion proteins: mediation by type 2 CD8+ T cells and dependence on IL-4 production.
abstract: CD28 signals contribute to either type 1 or type 2 T cell differentiation. Here, we show that administration of B7.2-Ig fusion proteins to tumor-bearing mice induces tumor regression by promoting the differentiation of antitumor type 2 CD8(+) effector T cells along with IL-4 production. B7.2-Ig-mediated regression was not induced in IL-4(-/-) and STAT6(-/-) mice. However, it was elicited in IFN-gamma(-/-) and STAT4(-/-) mice. By contrast, IL-12-induced tumor regression occurred in IL-4(-/-) and STAT6(-/-) mice, but not in IFN-gamma(-/-) and STAT4(-/-) mice. Moreover, B7.2-Ig treatment was effective in a tumor model not responsive to IL-12. B7.2-Ig administration elicited elevated levels of IL-4 production. Tumor regression was predominantly mediated by CD8(+) T cells, although the induction of these effector cells required CD4(+) T cells. Tumor regression induced by CD8(+) T cells alone was inhibited by neutralizing the IL-4 produced during B7.2-Ig treatment. Thus, these results indicate that stimulation in vivo of CD28 with B7.2-Ig in tumor-bearing mice results in enhanced induction of antitumor type 2 CD8(+) T cells (Tc2) leading to Tc2-mediated tumor regression.
authors.affiliation: Department of Oncology, Osaka University Graduate School of Medicine, Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Hiraoka
authors.forename: Takao
authors.initials: T
authors.lastname: Mukai
authors.forename: Noritami
authors.initials: N
authors.lastname: Takeuchi
authors.forename: Xu-Yu
authors.initials: XY
authors.lastname: Zhou
authors.forename: Shiro
authors.initials: S
authors.lastname: Ono
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Kogo
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Dunussi-Joannopoulos
authors.forename: Vincent
authors.initials: V
authors.lastname: Ling
authors.forename: Stanley
authors.initials: S
authors.lastname: Wolf
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D060945:Inducible T-Cell Co-Stimulator Ligand; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000008:administration & dosage; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000172:deficiency / Q000276:immunology / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011506:Proteins / Q000008:administration & dosage / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000627:therapeutic use; D012074:Remission Induction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; C400230:Icosl protein, mouse; D007141:Immunoglobulin Fc Fragments; D060945:Inducible T-Cell Co-Stimulator Ligand; D008562:Membrane Glycoproteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D015847:Interleukin-4