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Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells


Krebs, DL; Chehal, MK; Sio, A; Huntington, ND; Da, ML; Ziltener, P; Inglese, M; Kountouri, N; Priatel, JJ; Jones, J; Tarlinton, DM; Anderson, GP; Hibbs, ML; Harder, KW
2012-05-15
JOURNAL OF IMMUNOLOGY
Journal Article
188
10
5094-5105
The innate immune response is a first line of defense against invading pathogens; however, the magnitude of this response must be tightly regulated, as hyper- or suboptimal responses can be detrimental to the host. Systemic inflammation resulting from bacterial infection can lead to sepsis, which remains a serious problem with high mortality rates. Lyn tyrosine kinase plays a key role in adaptive immunity, although its role in innate immunity remains unclear. In this study, we show that Lyn gain-of-function (Lyn(up/up)) mice display enhanced sensitivity to endotoxin and succumb to upregulated proinflammatory cytokine production at a dose well tolerated by control animals. Endotoxin sensitivity in Lyn(up/up) mice depends on dendritic cells (DCs) and NK cells and occurs though a mechanism involving increased maturation and activation of the DC compartment, leading to elevated production of IFN-gamma by NK cells. We further show that modulation of endotoxin-induced signal transduction in DCs by Lyn involves the phosphatases Src homology 2 domain-containing phosphatase-1 and SHIP-1. Collectively, we demonstrate that Lyn regulates DC physiology such that alterations in Lyn-dependent signaling have profound effects on the nature and magnitude of inflammatory responses. Our studies highlight how perturbations in signaling pathways controlling DC/NK cell-regulated responses to microbial products can profoundly affect the magnitude of innate immune responses. The Journal of Immunology, 2012, 188: 5094-5105.
AMER ASSOC IMMUNOLOGISTS
NATURAL-KILLER-CELLS; NF-KAPPA-B; SRC-FAMILY KINASES; NECROSIS-FACTOR-ALPHA; TYROSINE KINASE; DEFICIENT MICE; INTERFERON-GAMMA; NEGATIVE REGULATION; AUTOIMMUNE-DISEASE; IFN-GAMMA
Immunology
10.4049/jimmunol.1103395
Copyright © 2012 by The American Association of Immunologists, Inc.