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

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

doi:10.1016/j.immuni.2018.03.012

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

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

Research output: Contribution to journal › Article › peer-review

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Abstract

Cerebral malaria is a deadly complication of Plasmodium infection and involves blood brain barrier (BBB) disruption following infiltration of white blood cells. During experimental cerebral malaria (ECM), mice inoculated with Plasmodium berghei ANKA-infected red blood cells develop a fatal CM-like disease caused by CD8⁺ T cell-mediated pathology. We found that treatment with interleukin-15 complex (IL-15C) prevented ECM, whereas IL-2C treatment had no effect. IL-15C-expanded natural killer (NK) cells were necessary and sufficient for protection against ECM. IL-15C treatment also decreased CD8⁺ T cell activation in the brain and prevented BBB breakdown without influencing parasite load. IL-15C induced NK cells to express IL-10, which was required for IL-15C-mediated protection against ECM. Finally, we show that ALT-803, a modified human IL-15C, mediates similar induction of IL-10 in NK cells and protection against ECM. These data identify a regulatory role for cytokine-stimulated NK cells in the prevention of a pathogenic immune response. NK cells can display both pro-inflammatory and regulatory function, but their role in the pathogenesis of malaria is not fully understood. Burrack et al. demonstrate that IL-15 complex (IL-15C) therapy prevents mice from succumbing to experimental cerebral malaria (ECM). IL-15C treatment stimulates NK cells to produce IL-10, suppressing the pathogenic CD8⁺ T cell response during ECM.

Original language	English (US)
Pages (from-to)	760-772.e4
Journal	Immunity
Volume	48
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2018.03.012
State	Published - Apr 17 2018

Bibliographical note

Funding Information:
We thank Susan Pierce, PhD for parasites and advice. We thank Kristin Hogquist, PhD, and Thomas Morrison, PhD, for advice and critical review of the manuscript. This project was supported by a Grant-in-Aid from the University of Minnesota Office of the Vice President for Research (108127 to S.E.H.) and NIH grants R21-AI100088 (S.C.J. and S.E.H.), F32-AI120312-01 (K.S.B.), R56-NS094150 (A.J.J.), and T32-AI7425-19 (M.A.H.).

Funding Information:
We thank Susan Pierce, PhD for parasites and advice. We thank Kristin Hogquist, PhD, and Thomas Morrison, PhD, for advice and critical review of the manuscript. This project was supported by a Grant-in-Aid from the University of Minnesota Office of the Vice President for Research ( 108127 to S.E.H.) and NIH grants R21-AI100088 (S.C.J. and S.E.H.), F32-AI120312-01 (K.S.B.), R56-NS094150 (A.J.J.), and T32-AI7425-19 (M.A.H.).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

CD8 T cells
IL-10
IL-15
NK cells
cerebral malaria
cytokine complexes
immunopathology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2018.03.012

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906161

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Burrack, K. S., Huggins, M. A., Taras, E., Dougherty, P., Henzler, C. M., Yang, R., Alter, S., Jeng, E. K., Wong, H. C., Felices, M., Cichocki, F., Miller, J. S., Hart, G. T., Johnson, A. J., Jameson, S. C., & Hamilton, S. E. (2018). Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells. Immunity, 48(4), 760-772.e4. https://doi.org/10.1016/j.immuni.2018.03.012

Burrack, KS, Huggins, MA, Taras, E, Dougherty, P, Henzler, CM , Yang, R, Alter, S, Jeng, EK, Wong, HC, Felices, M , Cichocki, F , Miller, JS , Hart, GT, Johnson, AJ, Jameson, SC & Hamilton, SE 2018, 'Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells', Immunity, vol. 48, no. 4, pp. 760-772.e4. https://doi.org/10.1016/j.immuni.2018.03.012

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

abstract = "Cerebral malaria is a deadly complication of Plasmodium infection and involves blood brain barrier (BBB) disruption following infiltration of white blood cells. During experimental cerebral malaria (ECM), mice inoculated with Plasmodium berghei ANKA-infected red blood cells develop a fatal CM-like disease caused by CD8+ T cell-mediated pathology. We found that treatment with interleukin-15 complex (IL-15C) prevented ECM, whereas IL-2C treatment had no effect. IL-15C-expanded natural killer (NK) cells were necessary and sufficient for protection against ECM. IL-15C treatment also decreased CD8+ T cell activation in the brain and prevented BBB breakdown without influencing parasite load. IL-15C induced NK cells to express IL-10, which was required for IL-15C-mediated protection against ECM. Finally, we show that ALT-803, a modified human IL-15C, mediates similar induction of IL-10 in NK cells and protection against ECM. These data identify a regulatory role for cytokine-stimulated NK cells in the prevention of a pathogenic immune response. NK cells can display both pro-inflammatory and regulatory function, but their role in the pathogenesis of malaria is not fully understood. Burrack et al. demonstrate that IL-15 complex (IL-15C) therapy prevents mice from succumbing to experimental cerebral malaria (ECM). IL-15C treatment stimulates NK cells to produce IL-10, suppressing the pathogenic CD8+ T cell response during ECM.",

keywords = "CD8 T cells, IL-10, IL-15, NK cells, cerebral malaria, cytokine complexes, immunopathology",

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

note = "Funding Information: We thank Susan Pierce, PhD for parasites and advice. We thank Kristin Hogquist, PhD, and Thomas Morrison, PhD, for advice and critical review of the manuscript. This project was supported by a Grant-in-Aid from the University of Minnesota Office of the Vice President for Research (108127 to S.E.H.) and NIH grants R21-AI100088 (S.C.J. and S.E.H.), F32-AI120312-01 (K.S.B.), R56-NS094150 (A.J.J.), and T32-AI7425-19 (M.A.H.). Funding Information: We thank Susan Pierce, PhD for parasites and advice. We thank Kristin Hogquist, PhD, and Thomas Morrison, PhD, for advice and critical review of the manuscript. This project was supported by a Grant-in-Aid from the University of Minnesota Office of the Vice President for Research ( 108127 to S.E.H.) and NIH grants R21-AI100088 (S.C.J. and S.E.H.), F32-AI120312-01 (K.S.B.), R56-NS094150 (A.J.J.), and T32-AI7425-19 (M.A.H.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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doi = "10.1016/j.immuni.2018.03.012",

language = "English (US)",

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AU - Burrack, Kristina S.

AU - Huggins, Matthew A.

AU - Taras, Emily

AU - Dougherty, Philip

AU - Henzler, Christine M.

AU - Yang, Rendong

AU - Alter, Sarah

AU - Jeng, Emily K.

AU - Wong, Hing C.

AU - Felices, Martin

AU - Cichocki, Frank

AU - Miller, Jeffrey S.

AU - Hart, Geoffrey T.

AU - Johnson, Aaron J.

AU - Jameson, Stephen C.

AU - Hamilton, Sara E.

N1 - Funding Information: We thank Susan Pierce, PhD for parasites and advice. We thank Kristin Hogquist, PhD, and Thomas Morrison, PhD, for advice and critical review of the manuscript. This project was supported by a Grant-in-Aid from the University of Minnesota Office of the Vice President for Research (108127 to S.E.H.) and NIH grants R21-AI100088 (S.C.J. and S.E.H.), F32-AI120312-01 (K.S.B.), R56-NS094150 (A.J.J.), and T32-AI7425-19 (M.A.H.). Funding Information: We thank Susan Pierce, PhD for parasites and advice. We thank Kristin Hogquist, PhD, and Thomas Morrison, PhD, for advice and critical review of the manuscript. This project was supported by a Grant-in-Aid from the University of Minnesota Office of the Vice President for Research ( 108127 to S.E.H.) and NIH grants R21-AI100088 (S.C.J. and S.E.H.), F32-AI120312-01 (K.S.B.), R56-NS094150 (A.J.J.), and T32-AI7425-19 (M.A.H.). Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/4/17

Y1 - 2018/4/17

N2 - Cerebral malaria is a deadly complication of Plasmodium infection and involves blood brain barrier (BBB) disruption following infiltration of white blood cells. During experimental cerebral malaria (ECM), mice inoculated with Plasmodium berghei ANKA-infected red blood cells develop a fatal CM-like disease caused by CD8+ T cell-mediated pathology. We found that treatment with interleukin-15 complex (IL-15C) prevented ECM, whereas IL-2C treatment had no effect. IL-15C-expanded natural killer (NK) cells were necessary and sufficient for protection against ECM. IL-15C treatment also decreased CD8+ T cell activation in the brain and prevented BBB breakdown without influencing parasite load. IL-15C induced NK cells to express IL-10, which was required for IL-15C-mediated protection against ECM. Finally, we show that ALT-803, a modified human IL-15C, mediates similar induction of IL-10 in NK cells and protection against ECM. These data identify a regulatory role for cytokine-stimulated NK cells in the prevention of a pathogenic immune response. NK cells can display both pro-inflammatory and regulatory function, but their role in the pathogenesis of malaria is not fully understood. Burrack et al. demonstrate that IL-15 complex (IL-15C) therapy prevents mice from succumbing to experimental cerebral malaria (ECM). IL-15C treatment stimulates NK cells to produce IL-10, suppressing the pathogenic CD8+ T cell response during ECM.

AB - Cerebral malaria is a deadly complication of Plasmodium infection and involves blood brain barrier (BBB) disruption following infiltration of white blood cells. During experimental cerebral malaria (ECM), mice inoculated with Plasmodium berghei ANKA-infected red blood cells develop a fatal CM-like disease caused by CD8+ T cell-mediated pathology. We found that treatment with interleukin-15 complex (IL-15C) prevented ECM, whereas IL-2C treatment had no effect. IL-15C-expanded natural killer (NK) cells were necessary and sufficient for protection against ECM. IL-15C treatment also decreased CD8+ T cell activation in the brain and prevented BBB breakdown without influencing parasite load. IL-15C induced NK cells to express IL-10, which was required for IL-15C-mediated protection against ECM. Finally, we show that ALT-803, a modified human IL-15C, mediates similar induction of IL-10 in NK cells and protection against ECM. These data identify a regulatory role for cytokine-stimulated NK cells in the prevention of a pathogenic immune response. NK cells can display both pro-inflammatory and regulatory function, but their role in the pathogenesis of malaria is not fully understood. Burrack et al. demonstrate that IL-15 complex (IL-15C) therapy prevents mice from succumbing to experimental cerebral malaria (ECM). IL-15C treatment stimulates NK cells to produce IL-10, suppressing the pathogenic CD8+ T cell response during ECM.

KW - CD8 T cells

KW - IL-10

KW - IL-15

KW - NK cells

KW - cerebral malaria

KW - cytokine complexes

KW - immunopathology

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

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