Rapid loss of group 1 innate lymphoid cells during blood stage Plasmodium infection

Abstract

ObjectivesInnate lymphoid cells (ILCs) share many characteristics with CD4+ T cells, and group 1 ILCs share a requirement for T‐bet and the ability to produce IFNγ with T helper 1 (Th1) cells. Given this similarity, and the importance of Th1 cells for protection against intracellular protozoan parasites, we aimed to characterise the role of group 1 ILCs during Plasmodium infection.MethodsWe quantified group 1 ILCs in peripheral blood collected from subjects infected with with Plasmodium falciparum 3D7 as part of a controlled human malaria infection study, and in the liver and spleens of Pc AS‐infected mice. We used genetically‐modified mouse models, as well as cell‐depletion methods in mice to characterise the role of group 1 ILCs during Pc AS infection.ResultsIn a controlled human malaria infection study, we found that the frequencies of circulating ILC1s and NK cells decreased as infection progressed but recovered after volunteers were treated with antiparasitic drug. A similar observation was made for liver and splenic ILC1s in P. chabaudi chabaudi AS (Pc AS)‐infected mice. The decrease in mouse liver ILC1 frequencies was associated with increased apoptosis. We also identified a population of cells within the liver and spleen that expressed both ILC1 and NK cell markers, indicative of plasticity between these two cell lineages. Studies using genetic and cell‐depletion approaches indicated that group 1 ILCs have a limited role in antiparasitic immunity during Pc AS infection in mice.DiscussionOur results are consistent with a previous study indicating a limited role for natural killer (NK) cells during Plasmodium chabaudi infection in mice. Additionally, a recent study reported the redundancy of ILCs in humans with competent B and T cells. Nonetheless, our results do not rule out a role for group 1 ILCs in human malaria in endemic settings given that blood stage infection was initiated intravenously in our experimental models, and thus bypassed the liver stage of infection, which may influence the immune response during the blood stage.ConclusionOur results show that ILC1s are lost early during mouse and human malaria, and this observation may help to explain the limited role for these cells in controlling blood stage infection.

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

“…Human CD1d was generated in modified human embryonic kidney 293S cells (HEK293S cells) and enzymatically biotinylated as previously described . Biotinylated monomeric CD1d was loaded with α‐GalCer (0.5% [v/v] tyloxapol in TBS) by incubation overnight at 37°C at a 6:1 molar ratio (α‐GalCer:CD1d).…”

Innate Lymphoid Cells in Protection, Pathology, and Adaptive Immunity During Apicomplexan Infection

“…Interestingly, although parasite burden was increased, T-bet deficiency reduced the severity of CM suggesting that T-bet dependent ILC1 development and activation could also cause immunopathology. A recent study indicates that NK cells and ILC1 are lost in peripheral blood of humans infected with Plasmodium falciparum and spleens and livers of mice infected with Plasmodium chaubaudi chabaudi AS (85). Using NKp46-iCre mice crossed onto myeloid cell leukemia sequence-1 floxed mice (Mcl1) to genetically ablate mature NK cells, there was no difference in parasitemia compared to WT controls.…”

“…infection. Overall, even though a recent study suggests that ILCs are irrelevant (85), there are still substantial gaps in knowledge about ILCs and Plasmodium spp. that would be important to investigate.…”

Contributions of natural killer cells to the immune response against Plasmodium

“…Using Plasmodium chabaudi or P. yoelii 17X infection as models of blood stage infection, NK cell frequencies increase [60] as does their production of IFNγ and TNF [40]. Depletion of NK cells with anti-NK1.1 or anti-asialo GM1 Ab resulted in increased mortality, decreased IFNγ, and either slightly increased or no change in parasitaemia levels [22, 61, 62]. These data suggest that NK cells may contribute to control of parasitaemia and/or disease development during P.c.…”