Previous reports have shown that γδ T cells are important for the elimination of malaria parasites in humans and mice. However, how γδ T cells are involved in protective immunity against blood-stage malaria remains unknown. We infected γδ T-cell–deficient (TCRδ-KO) mice and control wild-type mice with Plasmodium berghei XAT, which is a nonlethal strain. Although infected red blood cells were eliminated within 30 d after infection, TCRδ-KO mice could not clear the infected red blood cells, showed high parasitemia, and eventually died. Therefore, γδ T cells are essential for clearance of the parasites. Here, we found that γδ T cells play a key role in dendritic cell activation after Plasmodium infection. On day 5 postinfection, γδ T cells produced IFN-γ and expressed CD40 ligand during dendritic cell activation. These results suggest that γδ T cells enhance dendritic cell activation via IFN-γ and CD40 ligand–CD40 signaling. This hypothesis is supported strongly by the fact that in vivo induction of CD40 signaling prevented the death of TCRδ-KO mice after infection with P . berghei XAT. This study improves our understanding of protective immunity against malaria and provides insights into γδ T-cell–mediated protective immunity against various infectious diseases.

Malaria is caused by infection with Plasmodium parasites. Various studies with knockout mice have indicated that IFN-γ plays essential roles in protective immunity against blood-stage Plasmodium infection. However, after Plasmodium infection, increased IFN-γ production by various types of cells is involved not only in protective immunity, but also in immunopathology. Recent reports have shown that IFN-γ acts as a pro-inflammatory cytokine to induce not only the activation of macrophages, but also the generation of uncommon myelolymphoid progenitor cells after Plasmodium infection. However, the effects of IFN-γ on hematopoietic stem cells and progenitor cells are unclear. Therefore, the regulation of hematopoiesis by IFN-γ during Plasmodium infection remains to be clarified. Although there are conflicting reports concerning the significance of γδ T cells in protective immunity against Plasmodium infection, γδ T cells may respond to infection and produce IFN-γ as innate immune cells in the early phase of blood-stage malaria. Our recent studies have shown that γδ T cells express CD40 ligand and produce IFN-γ after Plasmodium infection, resulting in the enhancement of dendritic cell activation as part of the immune response to eliminate Plasmodium parasites. These data suggest that the function of γδ T cells is similar to that of NK cells. Although several reports suggest that γδ T cells have the potential to act as memory cells for various infections, it remains to be determined whether memory γδ T cells are generated by Plasmodium infection and whether memory γδ T cells can contribute to the host defense against re-infection with Plasmodium. Here, we summarize and discuss the effects of IFN-γ and the various functions of γδ T cells in blood-stage Plasmodium infection.

Tumors or embryonic stem cells bearing foreign mitochondrial DNA are rejected by the innate immune system via a mechanism that depends on MyD88.

γδ T cells play a crucial role in controlling malaria parasites. Dendritic cell (DC) activation via CD40 ligand (CD40L)-CD40 signaling by γδ T cells induces protective immunity against the blood-stage Plasmodium berghei XAT (PbXAT) parasites in mice. However, it is unknown which γδ T-cell subset has an effector role and is required to control the Plasmodium infection. Here, using antibodies to deplete TCR Vγ1 cells, we saw that Vγ1 γδ T cells were important for the control of PbXAT infection. Splenic Vγ1 γδ T cells preferentially expand and express CD40L, and both Vγ1 and Vγ4 γδ T cells produce IFN-γ during infection. Although expression of CD40L on Vγ1 γδ T cells is maintained during infection, the IFN-γ positivity of Vγ1 γδ T cells is reduced in late-phase infection due to γδ T-cell dysfunction. In Plasmodium-infected IFN-γ signaling-deficient mice, DC activation is reduced, resulting in the suppression of γδ T-cell dysfunction and the dampening of γδ T-cell expansion in the late phase of infection. Our data suggest that Vγ1 γδ T cells represent a major subset responding to PbXAT infection and that the Vγ1 γδ T-cell response is dependent on IFN-γ-activated DCs.

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Interleukin- (IL-) 10, anti-inflammatory cytokine, is known to inhibit the protective immune responses against malaria parasites and to be involved in exacerbating parasitemia during Plasmodium infection. In contrast, IL-10 is regarded as necessary for suppressing severe pathology during Plasmodium infection. Here, we summarize the role of IL-10 during murine malaria infection, focusing especially on coinfection with lethal and nonlethal strains of malaria parasites. Recent studies have demonstrated that the major sources of IL-10 are subpopulations of CD4+ T cells in humans and mice infected with Plasmodium. We also discuss the influence of innate immunity on the induction of CD4+ T cells during murine malaria coinfection.

Mixed infection with different Plasmodium species is often observed in endemic areas, and the infection with benign malaria parasites such as Plasmodium vivax or P. malariae has been considered to reduce the risk of developing severe pathogenesis caused by P. falciparum. However, it is still unknown how disease severity is reduced in hosts during coinfection. In the present study, we investigated the influence of coinfection with nonlethal parasites, P. berghei XAT (Pb XAT) or P. yoelii 17X (Py 17X), on the outcome of P. berghei NK65 (Pb NK65) lethal infection, which caused high levels of parasitemia and severe pathogenesis in mice. We found that the simultaneous infection with nonlethal Pb XAT or Py 17X suppressed high levels of parasitemia, liver injury, and body weight loss caused by Pb NK65 infection, induced high levels of reticulocytemia, and subsequently prolonged survival of mice. In coinfected mice, the immune response, including the expansion of B220intCD11c+ cells and CD4+ T cells and expression of IL-10 mRNA, was comparable to that in nonlethal infection. Moreover, the suppression of liver injury and body weight loss by coinfection was reduced in IL-10−/− mice, suggesting that IL-10 plays a role for a reduction of severity by coinfection with nonlethal malaria parasites.