IL-22 dampens the T cell response in experimental malaria

CD8+ T cells are key players during infection with the malaria parasite Plasmodium berghei ANKA (PbA). While they cannot provide protection against blood-stage parasites, they can cause immunopathology, thus leading to the severe manifestation of cerebral malaria. Hence, the tight control of CD8+ T cell function is key in order to prevent fatal outcomes. One major mechanism to control CD8+ T cell activation, proliferation and effector function is the integration of co-inhibitory and co-stimulatory signals. In this study, we show that one such pathway, the HVEM-CD160 axis, significantly impacts CD8+ T cell regulation and thereby the incidence of cerebral malaria. Here, we show that the co-stimulatory molecule HVEM is indeed required to maintain CD8+ T effector populations during infection. Additionally, by generating a CD160−/− mouse line, we observe that the HVEM ligand CD160 counterbalances stimulatory signals in highly activated and cytotoxic CD8+ T effector cells, thereby restricting immunopathology. Importantly, CD160 is also induced on cytotoxic CD8+ T cells during acute Plasmodium falciparum malaria in humans. In conclusion, CD160 is specifically expressed on highly activated CD8+ T effector cells that are harmful during the blood-stage of malaria.

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“…Splenocytes were isolated as described previously ( 35 ). Blood was collected using heparinized syringes and washed in PBS.…”

Section: Methodsmentioning

confidence: 99%

HVEM and CD160: Regulators of Immunopathology During Malaria Blood-Stage

et al. 2018

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“…Plasmodium berghei ANKA infected red blood cells were stored in liquid nitrogen in a solution containing 0.9% NaCl, 4.6% sorbitol and 35% glycerol. Infection was performed as previously described 45 . Briefly, C57BL/6 mice were infected with Plasmodium berghei ANKA-infected red blood cells intraperitoneally (i.p.)…”

Section: Methodsmentioning

confidence: 99%

Flt3 ligand expands bona fide innate lymphoid cell precursors in vivo

Parigi

Czarnewski

Das

et al. 2018

Sci Rep

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A common helper-like innate lymphoid precursor (CHILP) restricted to the innate lymphoid cells (ILC) lineage has been recently characterized. While specific requirements of transcription factors for CHILPs development has been partially described, their ability to sense cytokines and react to peripheral inflammation remains unaddressed. Here, we found that systemic increase in Flt3L levels correlated with the expansion of Lineage (Lin)negα4β7+ precursors in the adult murine bone marrow. Expanded Linnegα4β7+ precursors were bona fide CHILPs as seen by their ability to differentiate into all helper ILCs subsets but cNK in vivo. Interestingly, Flt3L-expanded CHILPs transferred into lymphopenic mice preferentially reconstituted the small intestine. While we did not observe changes in serum Flt3L during DSS-induced colitis in mice or plasma from inflammatory bowel disease (IBD) patients, elevated Flt3L levels were detected in acute malaria patients. Interestingly, while CHILP numbers were stable during the course of DSS-induced colitis, they expanded following increased serum Flt3L levels in malaria-infected mice, hence suggesting a role of the Flt3L-ILC axis in malaria. Collectively, our results indicate that Flt3L expands CHILPs in the bone marrow, which might be associated with specific inflammatory conditions.

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“…Two independent studies have demonstrated that in the absence of IL-22 (IL-22 KO mice) pathology cause by Plasmodium spp. infection is more severe (88, 92). Again, whether this IL-22 is coming from ILC3 is not known.…”

Section: Ilc and Plasmodiummentioning

confidence: 99%

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

et al. 2019

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Apicomplexans are a diverse and complex group of protozoan pathogens including Toxoplasma gondii, Plasmodium spp., Cryptosporidium spp., Eimeria spp., and Babesia spp. They infect a wide variety of hosts and are a major health threat to humans and other animals. Innate immunity provides early control and also regulates the development of adaptive immune responses important for controlling these pathogens. Innate immune responses also contribute to immunopathology associated with these infections. Natural killer (NK) cells have been for a long time known to be potent first line effector cells in helping control protozoan infection. They provide control by producing IL-12 dependent IFNγ and killing infected cells and parasites via their cytotoxic response. Results from more recent studies indicate that NK cells could provide additional effector functions such as IL-10 and IL-17 and might have diverse roles in immunity to these pathogens. These early studies based their conclusions on the identification of NK cells to be CD3–, CD49b+, NK1.1+, and/or NKp46+ and the common accepted paradigm at that time that NK cells were one of the only lymphoid derived innate immune cells present. New discoveries have lead to major advances in understanding that NK cells are only one of several populations of innate immune cells of lymphoid origin. Common lymphoid progenitor derived innate immune cells are now known as innate lymphoid cells (ILC) and comprise three different groups, group 1, group 2, and group 3 ILC. They are a functionally heterogeneous and plastic cell population and are important effector cells in disease and tissue homeostasis. Very little is known about each of these different types of ILCs in parasitic infection. Therefore, we will review what is known about NK cells in innate immune responses during different protozoan infections. We will discuss what immune responses attributed to NK cells might be reconsidered as ILC1, 2, or 3 population responses. We will then discuss how different ILCs may impact immunopathology and adaptive immune responses to these parasites.

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IL-22 dampens the T cell response in experimental malaria

Cited by 22 publications

References 60 publications

HVEM and CD160: Regulators of Immunopathology During Malaria Blood-Stage

HVEM and CD160: Regulators of Immunopathology During Malaria Blood-Stage

Flt3 ligand expands bona fide innate lymphoid cell precursors in vivo

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

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