Correction to: Determinant Roles of Dendritic Cell-expressed Notch Delta-like and Jagged Ligands on Anti-tumor T-cell Immunity

Background: Notch intercellular communication instructs tissue-specific T-cell development and function. In this study, we explored the roles of dendritic cell (DC)-expressed Notch ligands in the regulation of T-cell effector function. Methods: We generated mice with CD11c lineage-specific deletion of Notch Delta-like ligand (Dll)1 and Jagged (Jag)2. Using these genetically-ablated mice and engineered pharmacological Notch ligand constructs, the roles of various Delta-like and Jagged ligands in the regulation of T-cell-mediated immunity were investigated. We assessed tumor growth, mouse survival, cytokine production, immunophenotyping of myeloid and lymphoid populations infiltrating the tumors, expression of checkpoint molecules and T-cell function in the experimental settings of murine lung and pancreatic tumors and cardiac allograft rejection. Correlative studies were also performed for the expression of NOTCH ligands, NOTCH receptors and PD-1 on various subsets of myeloid and lymphoid cells in tumor-infiltrating immune cells analyzed from primary human lung cancers. Results: Mice with CD11c lineage-specific deletion of Notch ligand gene Dll1, but not Jag2, exhibited accelerated growth of lung and pancreatic tumors concomitant with decreased antigen-specific CD8+ T-cell functions and effector-memory (Tem) differentiation. Increased IL-4 but decreased IFN-γ production and elevated populations of T-regulatory and myeloid-derived suppressor cells were observed in Dll1-ablated mice. Multivalent clustered DLL1-triggered Notch signaling overcame DC Dll1 deficiency and improved anti-tumor T-cell responses, whereas the pharmacological interference by monomeric soluble DLL1 construct suppressed the rejection of mouse tumors and cardiac allograft. Moreover, monomeric soluble JAG1 treatment reduced T-regulatory cells and improved anti-tumor immune responses by decreasing the expression of PD-1 on CD8+ Tem cells. A significant correlation was observed between DC-expressed Jagged and Delta-like ligands with Tem-expressed PD-1 and Notch receptors, respectively, in human lung tumor-infiltrates.Conclusion: Our data show the importance of specific expression of Notch ligands on DCs in the regulation of Tcell effector function. Thus, strategies incorporating selectively engineered Notch ligands could provide a novel approach of therapeutics for modulating immunity in various immunosuppressive conditions including cancer. Keywords: Delta-like notch ligands, Jagged, Notch receptors, Lung carcinoma, Tumor infiltrating immune cells, Heart allograft rejection, Dendritic cells, CD8 T-cells, Regulatory T-cells, Cancer immunotherap

The lives and deaths of positrons in the interstellar medium

We reexamine in detail the various processes undergone by positrons in the ISM from their birth to their annihilation using the most recent results of positron interaction cross sections with H, H2 and He. The positrons' lives are divided into two phases: the 'in-flight' phase and the thermal phase. The first phase is treated with a Monte Carlo simulation that allows us to determine the fraction of positrons that form positronium and annihilate as well as the characteristics of the annihilation emission as a function of the medium conditions. The second phase is treated with a binary reaction rate approach, with cross sections adopted from experimental measurement or theoretical calculations. An extensive search and update of the knowledge of positron processes was thus undertaken. New reaction rates and line widths have been obtained. We investigate the treatment of the complicated interactions between positrons and interstellar dust grains. New reaction rates and widths of the line resulting from the annihilation inside and outside of the grain have been obtained. The final results of our calculations showed that dust is only important in the hot phase of the ISM, where it dominates all other processes. Combining the new calculations, we have constructed annihilation spectra for each phase of the ISM, considering various grain contents, as well as an overall combined spectrum for the ISM as a whole.Comment: 16 pages, 6 figures. accepted in Astronomy and Astrophysic