J Immunol 2002 Jul 1;169(1):151-158
Sfondrini L, Besusso D, Zoia MT, Rodolfo M, Invernizzi AM, Taniguchi M, Nakayama T, Colombo MP, Menard S, Balsari A.
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. 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 Valpha14/Vbeta8.2 mice that generate NKT cells; Jalpha281(-/-) 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 Jalpha281(-/-) 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 Jalpha281(-/-) 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 Valpha14 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.