Cutting Edge: The Mechanism of Invariant NKT Cell Responses to Viral Danger Signals

Abstract

Invariant NK T (iNKT) cells influence the response to viral infections, although the mechanisms are poorly defined. In this study we show that these innate-like lymphocytes secrete IFN-γ upon culture with CpG oligodeoxynucleotide-stimulated dendritic cells (DCs) from mouse bone marrow. This requires TLR9 signaling and IL-12 secretion by the activated DCs, but it does not require CD1d expression. iNKT cells also produce IFN-γ in response to mouse CMV infection. Their mechanism of mouse CMV detection is quite similar to that of CpG, requiring both TLR9 signaling and IL-12 secretion, while the need for CD1d expression is relatively minor. Consequently, iNKT cells have the ability to respond to a variety of microbes, including viruses, in an Ag-independent manner, suggesting they may play a broad role in antipathogen defenses despite their limited TCR repertoire.

NKT cells: Friend or foe during viral infections?

“…Two recent studies showed that MCMV infection induces iNKT cells to become activated and to produce IFN-g, which in turn amplifies the NK cell response. iNKT-cell activation is CD1d-independent but requires type I interferons and IL-12 [33,34]. During viral infections, these cytokines might be produced by activated DC and can activate iNKT independent of CD1d presentation.…”

“…Importantly, activation pathways independent of CD1d allow iNKT cells to respond to diverse infectious agents including viruses. Indeed, iNKT cells can be activated via soluble factors released by TLR-activated DC such as type I IFN or IL-12 [33,34], or by co-stimulatory molecules like OX40/OX40L [53].…”

Toll-Like Receptor 3 Ligand Dampens Liver Inflammation by Stimulating Vα14 Invariant Natural Killer T Cells to Negatively Regulate γδT Cells

“…2,13,14 The second model proposes that V␣14iNKT cells are indirectly acti- vated (in the absence of foreign antigen for the TCR) by IL-12 and/or IL-18 secreted by TLR (4,7,8,9)-stimulated antigen-presenting cells. 13,27,28,51,52 Thus, TLRs serve a critical role in the initiation of innate immunity in microbes. 13,14,27,28 Although TLR7, TLR8, and TLR9 are vital for the recognition of viruses [23][24][25][26] and indirectly induce V␣14iNKT cell activation, 27,51,52 the potential role of TLR3, an innate immune receptor that is also typically involved in sensing viral danger signals in mediation of V␣14iNKT cell activation remains undefined.…”

“…13,27,28,51,52 Thus, TLRs serve a critical role in the initiation of innate immunity in microbes. 13,14,27,28 Although TLR7, TLR8, and TLR9 are vital for the recognition of viruses [23][24][25][26] and indirectly induce V␣14iNKT cell activation, 27,51,52 the potential role of TLR3, an innate immune receptor that is also typically involved in sensing viral danger signals in mediation of V␣14iNKT cell activation remains undefined. The results presented in this study demonstrate an important role for the TLR3 ligand, poly I:C, in promoting hepatic V␣14iNKT cell activation (without prior activation by exogenous viral administration).…”

“…[23][24][25][26] An additional mechanism for activation of V␣14iNKT cells (in the absence of foreign antigen for their TCRs) is by IL-12 and/or IL-18 derived from antigen-presenting cells that have been activated via a TLR (4,7,8,9)-dependent pathway. 13,14,27,28 The precise pathway of activation may depend on the pathogen. For example, TLR4 traditionally recognizes the bacterial signal lipopolysaccharide, 22 whereas TLR7, TLR8, and TLR9 all sense viral signals.…”