IFN-γ-producing NKT cells exacerbate sepsis by enhancing C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils.
A role for NKT cells has been implicated in sepsis, but the mechanism by which NKT cells contribute to sepsis remains unclear. Here, we examined WT and NKT-cell-deficient mice of C57BL/6 background during cecal ligation and puncture-induced sepsis. The levels of C5a, IFN-γ, and IL-10 were higher in the serum and peritoneal fluid of WT mice than in those of CD1d(-/-) mice, while the mortality rate was lower in CD1d(-/-) mice than in WT mice. C5a blockade decreased mortality of WT mice during sepsis, whereas it did not alter that of CD1d(-/-) mice. As assessed by intracellular staining, NKT cells expressed IFN-γ, while neutrophils expressed IL-10. Upon coculture, IL-10-deficient NKT cells enhanced IL-10 production by WT, but not IFN-γR-deficient, neutrophils. Meanwhile, CD1d(-/-) mice exhibited high CD55 expression on neutrophils during sepsis, whereas those cells from WT mice expressed minimal levels of CD55. Recombinant IL-10 administration into CD1d(-/-) mice reduced CD55 expression on neutrophils. Furthermore, adoptive transfer of sorted WT, but not IFN-γ-deficient, NKT cells into CD1d(-/-) mice suppressed CD55 expression on neutrophils, but increased IL-10 and C5a levels. Taken together, IFN-γ-producing NKT cells enhance C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils, thereby exacerbating sepsis.
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea; Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Ji Hyung Kim, Program in Cellular and Molecular Medicine at Children's Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
Ji Hyung
JH
Kim
Sae Jin
SJ
Oh
Sehee
S
Ahn
Doo Hyun
DH
Chung
D000818:Animals; D055610:Antigens, CD1d / Q000502:physiology; D018958:CD55 Antigens / Q000502:physiology*; D015936:Complement C5a / Q000032:analysis / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000502:physiology*; D016753:Interleukin-10 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D018805:Sepsis / Q000276:immunology*
D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D018958:CD55 Antigens; C556062:IL10 protein, mouse; D016753:Interleukin-10; D015936:Complement C5a; D007371:Interferon-gamma
C5a; IFN-γ; NKT cell; Neutrophils; Sepsis