NK Cell Responses toPlasmodiumInfection and Control of Intrahepatic Parasite Development

Abstract

Various components of innate and adaptive immunity contribute to host defenses against Plasmodium infection. We investigated the contribution of NK cells to the immune response to primary infection with Plasmodium yoelii sporozoites in C57BL/6 mice. We found that hepatic and splenic NK cells were activated during infection and displayed different phenotypic and functional properties. The number of hepatic NK cells increased whereas the number of splenic NK cells decreased. Expression of the Ly49 repertoire was modified in the spleen but not in the liver. Splenic and hepatic NK cells have a different inflammatory cytokines profile production. In addition, liver NK cells were cytotoxic to YAC-1 cells and P. yoelii liver stages in vitro but not to erythrocytic stages. No such activity was observed with splenic NK cells from infected mice. These in vitro results were confirmed by the in vivo observation that Rag2−/− mice were more resistant to sporozoite infection than Rag2−/− γ c−/− mice, whereas survival rates were similar for the two strains following blood-stage infection. Thus, NK cells are involved in early immune mechanisms controlling Plasmodium infection, mostly at the pre-erythrocytic stage.

Macrophage-Mediated but Gamma Interferon-Independent Innate Immune Responses Control the Primary Wave ofPlasmodium yoeliiParasitemia

“…Thus, the inability to control lethal P. yoelii infection is only minimally affected by the absence of T cells and/or B cells with clonally rearranged antigen receptors. Moreover, and in agreement with previous studies in T-and B-cell-deficient animals (6,12,42), the course of PyNL infection in RAG Ϫ/Ϫ mice did not differ either significantly or reproducibly from that in WT mice up to 10 days p.i., indicating that antigen-specific T cells do not contribute significantly to control of the primary wave of parasitemia in nonlethal P. yoelii infection. As previously shown, however, RAG Ϫ/Ϫ mice were unable to control their infections over the long term with parasitemia rising steadily over a period of weeks (Fig.…”

“…Nevertheless, despite the distinct differences in NK cell and IFN-␥ responses evident during lethal and nonlethal P. yoelii infections, NK cell-depleted mice, although displaying slightly accelerated parasite numbers during lethal infection, did not display either increased ascending or peak parasite numbers during nonlethal infection, and IFN-␥ Ϫ/Ϫ mice were as susceptible or resistant to lethal or nonlethal infection, respectively, as WT mice were. Although it has previously been reported that NK cells are required for optimal resistance to PyNL in F 1 hybrid BALB/c ϫ C57BL/6 mice and in CB17 SCID mice (6, 10), a recent study in RAG Ϫ/Ϫ common ␥-chain Ϫ/Ϫ double knockout mice on a C57BL/6 background did not show a major role for NK cells during blood-stage PyNL infection (42). Additionally, a number of studies have provided conflicting reports on the importance of IFN-␥ during P. yoelii infection.…”

“…After several days (around 5 days in mice), IFN-␥ from ␣␤ T cells begins to dominate the response. It has been reported that NK cell-derived IFN-␥ contributes to the early control of Plasmodium chabaudi, Plasmodium berghei, and Plasmodium yoelii infections (6,10,21,30,31) and that NK cell depletion enhances the virulence of nonlethal P. yoelii and P. chabaudi infections (6,20,31), although the latter finding has recently been debated (42). Conversely, ␥␦ T cells play only a minor role in the control of the acute primary wave of malaria infection, as TCR␥␦ Ϫ/Ϫ or ␥␦ T-cell-depleted mice develop comparable peak parasitemia with little or no delay in parasite clearance (24,43).…”

“…The observation that primary peak parasitemia in T-celldeficient mice tends to be comparable to or lower than that of wild-type (WT) mice (10,27,42) is consistent with exacerbation of NK cell function in the absence of T cells, perhaps reflecting compensation for lack of T-and B-cell-mediated effector mechanisms and lack of homeostatic control from regulatory T cells (13,32). Exacerbation of innate immune responses in T-cell-deficient mice limits their utility for assessing the natural role of innate immune mechanisms; furthermore, studies in T-cell-deficient mice cannot address the possibility that induction of Th2 or regulatory T-cell responses, rather than lack of protective Th1 responses, may prevent control of virulent malaria infections.…”

Evolutionary struggles between NK cells and viruses

“…Although natural killer (NK) cells have been studied most extensively in terms of viral and tumour immunity, there is an increasing awareness that NK cells are activated, and in some situations potentially have a protective role, in immune responses to certain microorganisms, including Legionella pneumophila 109 122 and Plasmodium falciparum (reviewed in REF. 123 ).…”