title: IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function.
abstract: Interleukin 15 is essential for the development and differentiation of NK and memory CD8+(mCD8+) T cells. Our laboratory previously showed that NK and CD8+T lymphocytes facilitate the pathobiology of septic shock. However, factors that regulate NK and CD8+T lymphocyte functions during sepsis are not well characterized. We hypothesized that IL-15 promotes the pathogenesis of sepsis by maintaining NK and mCD8+T cell integrity. To test our hypothesis, the pathogenesis of sepsis was assessed in IL-15-deficient (IL-15 knockout, KO) mice. IL-15 KO mice showed improved survival, attenuated hypothermia, and less proinflammatory cytokine production during septic shock caused by cecal ligation and puncture or endotoxin-induced shock. Treatment with IL-15 superagonist (IL-15 SA, IL-15/IL-15Rα complex) regenerated NK and mCD8+T cells and re-established mortality of IL-15 KO mice during septic shock. Preventing NK cell regeneration attenuated the restoration of mortality caused by IL-15 SA. If given immediately prior to septic challenge, IL-15-neutralizing IgG M96 failed to protect against septic shock. However, M96 caused NK cell depletion if given 4 d prior to septic challenge and conferred protection. IL-15 SA treatment amplified endotoxin shock, which was prevented by NK cell or IFN-γ depletion. IL-15 SA treatment also exacerbated septic shock caused by cecal ligation and puncture when given after the onset of sepsis. In conclusion, endogenous IL-15 does not directly augment the pathogenesis of sepsis but enables the development of septic shock by maintaining NK cell numbers and integrity. Exogenous IL-15 exacerbates the severity of sepsis by activating NK cells and facilitating IFN-γ production.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212; and.
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Liming
authors.initials: L
authors.lastname: Luan
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Naeem K
authors.initials: NK
authors.lastname: Patil
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Jingbin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Bohannon
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212; and.
authors.forename: Whitney
authors.initials: W
authors.lastname: Rabacal
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212; and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fensterheim
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Antonio
authors.identifier: 0000-0003-1651-9037
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37212; and edward.r.sherwood@vanderbilt.edu.|Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sherwood
mesh_terms: D000818:Animals; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012772:Shock, Septic / Q000209:etiology* / Q000276:immunology
chemical_list: D019409:Interleukin-15; D007371:Interferon-gamma