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Published on: July 14, 2016
Immune Phenotypic Characterization of a TRAIL-Knockout Mouse
Ani K Stoyanova1, Arne Sattler1, Elisabeth M Hahn1
1Department of General, Visceral and Vascular Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.
Abstract:
The TNF-superfamily member TRAIL is known to mediate selective apoptosis in tumor cells suggesting this protein as a potential antitumor drug target. However, initial successful pr-clinical results could not be translated into the clinic. Reasons for the ineffectiveness of TRAIL-targeting in tumor therapies could include acquired TRAIL resistance. A tumor cell acquires TRAIL resistance, for example, by upregulation of antiapoptotic proteins. In addition, TRAIL can also influence the immune system and thus, tumor growth. We were able to show in our previous work that TRAIL-/- mice show improved survival in a mouse model of pancreatic carcinoma. Therefore, in this study we aimed to immunologically characterize the TRAIL-/- mice. We observed no significant differences in the distribution of CD3+, CD4+, CD8+ T-cells, Tregs, and central memory CD4+ and CD8+ cells. However, we provide evidence for relevant differences in the distribution of effector memory T-cells and CD8+CD122+ cells but also in dendritic cells. Our findings suggest that T-lymphocytes of TRAIL-/- mice proliferate at a lower rate, and that the administration of recombinant TRAIL significantly increases their proliferation, while regulatory T-cells (Tregs) from TRAIL-/- mice are less suppressive. Regarding the dendritic cells, we found more type-2 conventional dendritic cells (DC2s) in the TRAIL-/- mice. For the first time (to the best of our knowledge), we provide a comprehensive characterization of the immunological landscape of TRAIL-deficient mice. This will establish an experimental basis for future investigations of TRAIL-mediated immunology.
Insights
Mice lacking TNF-related apoptosis-inducing ligand (TRAIL) showed altered immune cell distribution and function, impacting T-cell proliferation and regulatory T-cell (Treg) suppressiveness, offering insights into TRAIL-based cancer therapies.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Medicine
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) targets tumor cells but faces clinical challenges due to resistance.
- TRAIL influences the immune system, affecting tumor growth and therapeutic outcomes.
- Previous studies indicated improved survival in TRAIL-deficient mice with pancreatic cancer.
Purpose of the Study:
- To comprehensively characterize the immunological landscape of TRAIL-deficient (TRAIL-/-) mice.
- To investigate the impact of TRAIL deficiency on immune cell populations and functions.
- To establish a foundation for future research on TRAIL's role in immunology and cancer therapy.
Main Methods:
- Flow cytometry analysis of T-cell subsets (CD3+, CD4+, CD8+, Tregs, memory cells) and dendritic cells.
- Assessment of T-lymphocyte proliferation rates in response to TRAIL.
- Evaluation of regulatory T-cell (Treg) suppressive function.
- Comparison of immune cell distribution between TRAIL-/- and wild-type mice.
Main Results:
- No significant differences in CD3+, CD4+, CD8+, Tregs, or central memory T-cells were observed.
- Significant alterations were found in effector memory T-cells, CD8+CD122+ cells, and dendritic cell populations.
- TRAIL-/- T-lymphocytes exhibited lower proliferation rates, which were increased by recombinant TRAIL.
- Regulatory T-cells from TRAIL-/- mice showed reduced suppressive activity.
- TRAIL-/- mice displayed an increased proportion of type-2 conventional dendritic cells (DC2s).
Conclusions:
- TRAIL deficiency leads to distinct changes in the distribution and function of specific immune cell subsets, including T-cells and dendritic cells.
- These immunological alterations in TRAIL-/- mice provide a basis for understanding TRAIL's complex role in immunity and cancer.
- The findings suggest potential immunomodulatory strategies involving TRAIL for cancer treatment.
