Absence of the CD1 molecule up-regulates antitumor activity induced by CpG oligodeoxynucleotides in mice.
The role of NKT cells on antitumor activity of CpG oligodeoxynucleotides (ODNs) was evaluated by peritumoral injections of CpG-ODNs in s.c. melanoma-bearing mice of strains differing in the number of NKT cells (athymic nude mice, recombination-activating gene(-/-)/transgenic V(alpha)14/Vbeta8.2 mice that generate NKT cells; J(alpha)281(-/-) mice and CD1(-/-) mice, which both have a strongly reduced number of NKT cells; and C57BL/6 wild-type mice). Tumor growth was significantly inhibited in strains enriched or depleted of NKT cells. The two murine strains having a reduced number of NKT cells differed significantly in the CpG-dependent tumor growth inhibition: in J(alpha)281(-/-) mice this inhibition was superimposable to that observed in C57BL/6 mice, while in CD1(-/-) mice the inhibition was dramatic. The increased tumor inhibition in CD1(-/-) correlated with a significantly higher ratio of IFN-gamma-IL-4 production in response to CpG as compared with C57BL/6 and J(alpha)281(-/-) mice. Experiments in which preparations of APCs and lymphocytes of the three strains were mixed showed that in the presence of APCs not expressing CD1, the production of CpG-ODN-induced type 1 cytokines was higher. Phenotype analysis of IFN-gamma- and IL-4-producing cells revealed that the differences between CD1(-/-) and C57BL/6 in the production of these two cytokines were mainly due to CD3(+) T lymphocytes. These data point to a regulatory role for the CD1 molecule in antitumor activity induced by danger signals, independently of V(alpha)14 NKT cells. The identification of a CD1-dependent suppressive subpopulation(s) might have important implications for the study of tolerance in the context of cancer, autoimmunity, and transplantation.
Sfondrini
Lucia
L
Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
Besusso
Dario
D
Zoia
Maria Teresa
MT
Rodolfo
Monica
M
Invernizzi
Anna Maria
AM
Taniguchi
Masaru
M
Nakayama
Toshinori
T
Colombo
Mario Paolo
MP
Ménard
Sylvie
S
Balsari
Andrea
A
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018949:Antigens, CD1 / Q000235:genetics* / Q000502:physiology; D018899:CpG Islands / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D016130:Immunophenotyping; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology*
D000276:Adjuvants, Immunologic; D018949:Antigens, CD1; C408982:CPG-oligonucleotide; D016207:Cytokines; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009838:Oligodeoxyribonucleotides; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D015847:Interleukin-4; D007371:Interferon-gamma