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* Molecular Targeting Unit,
Melanoma Genetics Unit, and
Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy;
CREST and Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; and
¶ Institute of Pathology, University of Milan, Milan, Italy
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
14/V
8.2 mice that generate NKT
cells; J281-/- 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 J281-/- 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-
-IL-4 production in response to
CpG as compared with C57BL/6 and J281-/- 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-- 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
V14 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.
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