Complement components modulate activation of mouse NK cells (134.67)

Abstract

Abstract Activation of TLR pathway and complement cascade are two critical defense mechanisms of the innate immune system recently found to interact and influence effector cell function. Natural killer (NK) cells, essential participants in anti-viral and anti-tumor responses, are activated by TLR-3, -4, -7, and -9 pathways via priming by dendritic cells. It is not known whether products of complement activation influence NK cell responses. To examine this possibility, we analyzed NK cell activation in mice lacking complement components or their receptors. Splenocytes from C3-/- mice had significantly more IFN-ã positive NK cells than C3+/+ mice (2-4 fold higher, P<0.01-0.05) when stimulated with PMA and ionomycin, or with TLR agonists: poly I:C (TLR3), Imiquinoid (TLR7), and LPS (TLR4). Increased NK cell activation by Poly IC was also evident in mice lacking C3a and C5a receptors (C3aR-/- 33%, C5aR-/- 45% vs. BALB/c WT 23% p<0.05). Furthermore, intravenous injection of CR2-Crry, an inhibitor of C3 convertase targeted to the sites of complement activation, markedly enhanced IFN-ã production in NK cells in response to poly I:C (CR2-Crry 35% vs PBS 17%, p<0.01). Our results indicate that NK cell activation was negatively regulated by complement components. Blockade of complement activation is a potential therapy to amplify NK cell responses and promote enhanced host defense against viral infections and tumors. This study is supported by NIH grant R01AI055007 awarded to Dr Jane Salmon.