Immune Phenotypic Characterization of a TRAIL-Knockout Mouse

SIMPLE SUMMARY: The role of the TNF-superfamily member TRAIL (TNF-related apoptosis inducing ligand) for potential interactions with the immunological tumor network is not completely understood. This article provides a comprehensive immune phenotype profile of a TRAIL-knockout (TRAIL(−/−)) mouse model and should serve as a tool to study the functional relevance of TRAIL in proof-of-concept studies. 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.