Induction of tumor regression by administration of B7-Ig fusion proteins: mediation by type 2 CD8+ T cells and dependence on IL-4 production.
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.
Yamaguchi
Nobuya
N
Department of Oncology, Osaka University Graduate School of Medicine, Yamada-oka, Suita, Osaka 565-0871, Japan.
Hiraoka
Shin-ichiro
S
Mukai
Takao
T
Takeuchi
Noritami
N
Zhou
Xu-Yu
XY
Ono
Shiro
S
Kogo
Mikihiko
M
Dunussi-Joannopoulos
Kyriaki
K
Ling
Vincent
V
Wolf
Stanley
S
Fujiwara
Hiromi
H
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*
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