Related Experiment Videos
Absence of the CD1 molecule up-regulates antitumor activity induced by CpG oligodeoxynucleotides in mice
Lucia Sfondrini1, Dario Besusso, Maria Teresa Zoia
1Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.
Abstract:
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.
Insights
CpG oligodeoxynucleotides (ODNs) demonstrate antitumor activity, with CD1 molecule regulation independent of NKT cells. This suggests CD1-dependent suppressive cells impact cancer, autoimmunity, and transplantation tolerance.
Area of Science:
- Immunology
- Cancer Research
- Cell Biology
Background:
- CpG oligodeoxynucleotides (ODNs) are known to activate immune responses.
- NKT cells play a role in antitumor immunity, but their precise role with CpG ODNs is unclear.
- The CD1 molecule's function in immune responses, particularly in relation to CpG ODNs and antitumor activity, requires further elucidation.
Purpose of the Study:
- To evaluate the role of NKT cells in the antitumor activity of CpG ODNs.
- To investigate the influence of CD1 molecule expression on CpG ODN-mediated antitumor effects.
- To identify immune cell populations responsible for mediating these effects.
Main Methods:
- Peritumoral injections of CpG-ODNs in mice with varying NKT cell numbers (athymic nude, RAG(-/-)/Vα14Tg, Jα281(-/-), CD1(-/-), and C57BL/6 wild-type).
- Tumor growth inhibition assessment.
- Analysis of cytokine production (IFN-γ, IL-4) in response to CpG.
- Mixed lymphocyte and APC experiments.
- Phenotype analysis of cytokine-producing cells (CD3+ T lymphocytes).
Main Results:
- Tumor growth was significantly inhibited in mice with altered NKT cell numbers.
- CpG-ODN-mediated tumor inhibition was dramatically enhanced in CD1(-/-) mice compared to other strains.
- Enhanced inhibition in CD1(-/-) mice correlated with a higher ratio of IFN-γ/IL-4 production.
- CD1-independent APCs promoted higher type 1 cytokine production.
- Differences in cytokine production were mainly attributed to CD3+ T lymphocytes.
Conclusions:
- The CD1 molecule plays a regulatory role in danger signal-induced antitumor activity, independent of Vα14 NKT cells.
- A CD1-dependent suppressive subpopulation may exist, influencing immune tolerance.
- These findings have implications for understanding tolerance in cancer, autoimmunity, and transplantation.