Interleukin-15 Enhances Innate and Adaptive Immune Responses to Blood-Stage Malaria Infection in Mice

Abstract

Compared to C57BL/6 wild-type mice, interleukin-15 ؊/؊ (IL-15 ؊/؊ ) mice showed delayed clearance of Plasmodium chabaudi AS infection, lower type 1 cytokine production, impaired dendritic cell and NK cell functions, and lower titers of malaria-specific antibodies. Thus, IL-15 supports early control and timely resolution of blood-stage malaria through promotion of Th1-dependent innate and adaptive immune responses.

Interaction of Mouse Dendritic Cells and Malaria-Infected Erythrocytes: Uptake, Maturation, and Antigen Presentation

“…In vitro maturation of DCs exposed to pRBCs but not to nRBCs also reflected in vivo maturation following P. chabaudi infection. These results are in agreement with other studies showing that splenic CD11c ϩ DCs from mice infected with P. chabaudi exhibit up-regulated expression of CD40, CD54, and CD86 (7), as well as increased production of IFN-␥ (7,24). Similarly, splenic CD11c ϩ DCs from mice infected with P. yoelii 17X stimulate high levels of IL-2, IFN-␥, and TNF-␣ production by responding naive CD4…”

“…The kinetics of DC uptake of pRBCs closely coincided with the level of IFN-␥ production observed in P. chabaudi-infected B6 mice (19,23). Notably, the peak level of pRBC uptake by splenic DCs observed in this study also coincided with peak numbers of splenic CD11c ϩ DCs expressing IFN-␥ at day 4 -5 following P. chabaudi infection (7,24). For macrophages, levels of nonopsonic phagocytosis also correlate with the ability of infected mice to produce IFN-␥ and treatment of macrophages with IFN-␥ in vitro enhances phagocytosis of pRBCs while treatment with IL-10 inhibits this activity.…”

“…This increased phagocytic activity may be due to an expansion of the DC population in the spleen following P. chabaudi infection (7,24). As the parasite replicates, causing the parasite burden to increase in the blood and more pRBCs to be deposited in the spleen for removal, blood-borne DCs are recruited to the spleen in increasing numbers.…”

“…Despite the lack of maturation in response to LPS, DCs pulsed with RBCs infected with P. yoelii or P. chabaudi were fully capable of inducing protective immunity against homologous challenge infection, suggesting that DC maturation is merely delayed rather than arrested in vitro (32). Studies showing inhibition of DC maturation and lower T cell stimulatory activity by Plasmodium parasites used DCs derived from human peripheral blood cells (12) or mouse BM precursors (13,32), while other studies (7)(8)(9)24), including the study presented here, showing up-regulated DC maturation and function used CD11c ϩ DCs purified from spleens of naive or infected mice. DCs grown in culture develop and interact with Plasmodium spp.…”

“…Given the importance of the spleen in host resistance to murine blood-stage Plasmodium parasites, the expansion of the splenic DC population (7,24) and migration of CD11c ϩ DCs to the T cell-rich zones of the spleen (7) following malaria infection suggest that splenic DCs are in a prime position to initiate protective immune responses against blood-stage malaria. DCs recognize foreign ligands through pattern recognition receptors, a process that could trigger their maturation as well as the production of proinflammatory cytokines.…”