IL-15 induces durable resident memory T cell formation and function following genetically attenuated Plasmodium vaccination in mice

Introduction/Rationale: Due to their immediate effector function and position in tissues, resident memory T (TDRM) cells are uniquely equipped to provide early defense against invading pathogens. Malaria is a major public health threat in need of a highly efficacious and durable vaccine. Following an infected mosquito bite, Plasmodium sporozoites (SPZ) travel to the liver and infect hepatocytes. Stopping infection at the liver stage prevents the disease-causing blood stage infection and transmission. Whole sporozoite vaccines, including genetically attenuated parasites (GAPs), induce liver CD8+ TDRM cells and are highly efficacious. However, manufacturing and deployment of these vaccines is incredibly resource intensive. Since liver TDRM formation depends on IL-15, we investigated the ability of IL-15 complex (IL-15C, IL-15 combined with IL-15Rα) to augment TDRM-mediated immunity in a mouse model of GAP vaccination.

Methods: We tested the impact of IL-15C on liver TDRM formation in the absence and presence of GAP vaccination by flow cytometric analysis of T cells in the spleen, liver and liver-draining lymph node. We tested the impact of IL-15C on vaccine efficacy by measuring liver parasite load following challenge with live SPZ.

Results: IL-15C transiently increases the number of liver CD8+ and CD4+ TDRM cells in the absence of antigen. In the context of GAP vaccination, IL-15C treatment results in a sustained increase in the number of liver CD8+ and CD4+ TDRM cells. Additionally, IL-15C enhances liver T cell functionality as measured by IFN-γ production following ex vivo simulation. Importantly, IL-15C treatment decreases parasite burden in the liver following SPZ challenge.

Conclusion: Overall, these findings improve our understanding of the mechanisms that increase TDRM cell numbers and function, which will inform vaccine strategy and facilitate greater control of malaria.