Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells

Burrack, Kristina S.; Huggins, Matthew A; Taras, Emily; Dougherty, Phillip M.; Henzler, Christine; Yang, Rendong; Alter, Sarah; Jeng, Emily K.; Wong, Hing C.; Felices, Martin; Cichocki, Frank; Miller, Jeffrey S.; Hart, Geoffrey T.; Johnson, Aaron J.; Jameson, Stephen C.; Hamilton, Sara E.

doi:10.1016/j.immuni.2018.03.012

Cited by 65 publications

(77 citation statements)

References 69 publications

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“…These studies are in line with other reports showing a collapse of TReg cells during acute T. gondii infection due to IL-2 starvation and an overall protective role of TRegs in acute T. gondiimediated immunopathogenesis [75][76][77][78]. In contrast to JES6-1A12-containing IL2C, S4B6containing IL2C has been shown to boost NK cell and memory CD8 + T cell numbers in mice and to enhance their cytolytic capacity against viral infections, malaria [79] and cancer cells [71,[80][81][82]. Short-term exposure of naïve mice to IL2C containing S4B6 has also been shown to enhance resistance and immunity against Listeria monocytogenes infection [83].…”

Section: Interventionssupporting

confidence: 91%

“…More recently, IL2C treatment has also been tested successfully in cancer models in combination with immune checkpoint blockade [88]. IL-15/IL-15Rα-Fc complexes (IL15C) have also been shown to expand CD8 + T cell, DN T cell and NK cell populations, and to protect mice against cerebral malaria via the induction of IL-10-producing NK cells [79]. Whether IL15C would also be protective in our model of lethal toxoplasmosis remains to be investigated.…”

Section: Interventionsmentioning

confidence: 99%

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Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

Kupz

Pai

Giacomin

et al. 2019

Preprint

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24Toxoplasmic encephalitis is an AIDS-defining condition in HIV + individuals. The decline of 25 IFN-γ-producing CD4 + T cells in AIDS is a major contributing factor in reactivation of 26 quiescent Toxoplasma gondii to an actively replicating stage of infection. Hence, it is important 27 to identify CD4-independent mechanisms to control acute T. gondii infection. Here we have 28 investigated the targeted expansion and regulation of IFN-γ production by CD8 + T cells, DN T 29 cells and NK cells in response to T. gondii infection using IL-2 complex (IL2C) pre-treatment 30 in an acute in vivo mouse model. Our results show that expansion of CD8 + T cells, DN T cells 31 and NK cell by S4B6 IL2C treatment increases survival rates of mice infected with T. gondii 32 and this increased survival is dependent on both IL-12-and IL-18-driven IFN-γ production. 33 Processing and secretion of IFN-γ-inducing, bioactive IL-18 is dependent on the sensing of 34 active parasite invasion by multiple redundant inflammasome sensors in multiple hematopoietic 35 cell types but independent from T. gondii-derived dense granule (GRA) proteins. Our results 36 provide evidence for a protective role of IL2C-mediated expansion of CD8 + T cells, DN T cells 37 and NK cells in murine toxoplasmosis and may represent a promising adjunct therapy for acute 38 toxoplasmosis. 39 40 41 3 Author Summary 42A third of the world's population is chronically infected with the parasite Toxoplasma gondii. 43 In most cases the infection is asymptomatic, but in individuals suffering from AIDS, 44 reactivation of brain and muscle cysts containing T. gondii is a significant cause of death. The 45 gradual decline of CD4 T cells, the hallmark of AIDS, is believed to be a major contributing 46 factor in reactivation of T. gondii infection and the development of acute disease. In this study, 47 we show that targeted expansion of non-CD4 immune cell subsets can prevent severe disease 48 and premature death via increased availability of interferon gamma-producing immune cells. 49 We also demonstrate that the upstream signaling molecule interleukin-18 is required for the 50 protective immune response by non-CD4 cells and show that the sensing of active parasite 51 invasion by danger recognition molecules is crucial. Our findings reveal that targeted cell 52 expansion may be a promising therapy in toxoplasmosis and suggests that the development of 53 novel intervention strategies targeting danger recognition pathways may be useful against 54 toxoplasmosis, particularly in the context of AIDS. 55 57 [1]. It is estimated that one-third of the world's population is infected with T. gondii. In most 58 individuals, infection is asymptomatic and leads to chronic, life-long persistence of T. gondii-59 containing cysts, primarily in brain and muscle tissue [2]. Active disease, also known as 60 toxoplasmosis, usually occurs after reactivation of encysted parasites, and is often associated 61 with immunosuppression. If untreated, toxoplasmosis may be fatal. Addi...

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Section: Interventionssupporting

confidence: 91%

Section: Interventionsmentioning

confidence: 99%

Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

Kupz

Pai

Giacomin

et al. 2019

Preprint

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“…IL-15 has been considered extremely promising as an anti-cancer agent, but some studies have indicated that it may be of greatest benefit in settings where IL-15 was combined with other approaches, including, for example, agents to relieve checkpoints, combination with anti-cancer monoclonal antibodies to augment ADCC, or in combination with agonistic anti-CD40 antibodies (Waldmann, 2018). IL-15 and IL-2 exhibit a range of differences, particularly in vivo, and antibody-bound IL-15 but not IL-2 could protect mice from cerebral malaria (Burrack et al, 2018).…”

Section: G C Family Cytokines and Translational Advancesmentioning

confidence: 99%

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

2019

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The common cytokine receptor g chain, g c , is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding g c results in X-linked severe combined immunodeficiency in humans, and g c family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.

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“…T cell-stimulating cytokines play essential roles in T cell activation and proliferation (7)(8)(9)(10)(11). Insufficient T cell growth factors inside the tumor microenvironment (TME) might contribute to the lack of TILs.…”

Section: Introductionmentioning

confidence: 99%

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

et al. 2020

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Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells

Cited by 65 publications

References 69 publications

Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

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