IL-15 induces durable resident memory T cell formation and function following genetically attenuated Plasmodium vaccination in mice 2306464

Abstract

Abstract Introduction 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. Funding Source NIH R21 R21AI182639; Falk Medical Research Trust Catalyst Award Topic Categories Vaccines and Immunotherapy (VAC)