Cytokines of the common γ-chain receptor family such as IL-15 are vital with respect to activating immune cells, sustaining healthy immune functions, and augmenting the anti-tumor activity of effector cells, making them ideal candidates for cancer immunotherapy. IL-15, either in its soluble form (IL-15sol) or complexed with IL-15Rα (IL-15Rc), has been shown to exhibit potent anti-tumor activities in various experimental cancer studies. Here we describe the impact of intraperitoneal IL-15 in a cancer cell-delivered IL-15 immunotherapy approach using the 70Z/3-L leukemia mouse model. Whereas both forms of IL-15 led to significantly improved survival rates compared to the parent cell line, there were striking differences in the extent of the improved survival: mice receiving cancer cells secreting IL-15sol showed significantly longer survival and protective long-term immunity compared to those producing IL-15Rc. Interestingly, injection of leukemia cells secreting IL-15sol lead to heightened expansion of CD4+ and CD8+ T-cell populations in the peritoneum compared to IL-15Rc. Cell-secreted IL-15Rc resulted in an influx and/or expansion of NK1.1+ cells in the peritoneum which was much less pronounced in the IL-15sol model. Furthermore, IL-15Rc but not IL-15sol lead to T-cell exhaustion and disease progression. To our knowledge, this is the first study detailing a significantly different biological effect of cell-delivered IL-15sol versus IL-15Rc in a mouse cancer immunotherapy study.

and A.K. designed flow cytometry and cell sorting experiments. B.A. and H.B.J. were responsible for participant enrollment, sample collection, and processing. Data generation and acquisition were performed by S.D. and analyzed by S.D., K.L.,

Few studies have investigated immune cell ontogeny throughout the period of increased vulnerability to infections in early life. Here, we evaluated the dynamics of two critical T cell populations, regulatory T (Treg) cells and Th17 cells, over the first 9 months of life. We observed that Treg and Th17 cells developed in a synchronous fashion. Infants exposed to HIV in utero (iHEU), who are more likely to develop infections, had a lower frequency of Tregs at birth and 36 weeks compared to HIV unexposed infants. This increased Th17/Treg ratio in iHEU was associated with impaired gut integrity at birth. These findings suggest that gut damage disrupts the Th17/Treg ratio during infant immune development, likely by attracting Treg cells to regulate inflammation occurring in the gut, so revealing an immune-gut nexus influenced by HIV exposure.