Interaction of Mycobacterium tuberculosis Cell Wall Components with the Human Natural Killer Cell Receptors NKp44 and Toll‐Like Receptor 2

Abstract

We have previously demonstrated that a soluble form of the human NK cell natural cytotoxicity receptor NKp44, binds to the surface of Mycobacterium tuberculosis (MTB). Herein, we investigated the interaction of MTB cell wall components (CWC) with NKp44 or with Toll-like receptor 2 (TLR2) and the role of NKp44 and TLR2 in the direct activation of NK cells upon stimulation with MTB CWC. By using several purified bacterial CWC in an ELISA, we demonstrated that NKp44 was able to bind to the MTB cell wall core mycolyl-arabinogalactan-peptidoglycan (mAGP) as well as to mycolic acids (MA) and arabinogalactan (AG), while soluble TLR2 bound to MTB peptidoglycan (PG), but not to MA or AG. The mAGP complex induced NK cell expression of CD25, CD69, NKp44 and IFN-c production at levels comparable to M. bovis Bacillus Calmette-Gu erin-stimulated (BCG) cells. While AG and MA used alone failed to induce NK cell activation, mycobacterial PG-exhibited NK cell stimulatory capacity. Activation of resting NK cells by mAGP and IFN-c production were inhibited by anti-TLR2 MAb, but not by anti-NKp44 MAb. Differently, anti-NKp44 MAb partially inhibited CD69 expression on NK cells pre-activated with IL-2 and then stimulated with mAGP or whole BCG. Overall, these results provide evidence that components abundant in mycobacterial cell wall are able to interact with NKp44 (AG, MA) and TLR-2 (PG), respectively. While interaction of TLR2 with mycobacterial cell wall promotes activation of resting NK cells and IFN-c production, NKp44 interaction with its putative ligands could play a secondary role in maintaining cell activation.

Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis

“…[51][52][53] Similar to our results, exposure of NK cells to TLR2 agonists was found to allow the induction of CD69 expression as well as the production of IFNg. 54,55 Of interest, unlike other studies reporting that different types of exosomes have the capability to trigger immune cell functions through different receptors belonging to TLR family, including TLR7, 8, 1 and 2, 38-41 only TLR2 is involved in the MM exosome-induced NK cell activation.…”

Human Monocyte-Derived Dendritic Cells Exposed to Microorganisms Involved in Hypersensitivity Pneumonitis Induce a Th1-Polarized Immune Response

“…Ligands that are present on nearly all fungi and might be responsible for stimulating the TLRs include ␤-glucans, mannans, and chitin (25). Several studies involving either the genus Mycobacterium (mostly Mycobacterium tuberculosis) or Gram-positive bacteria (but not specifically actinomycetes) also demonstrated interactions between bacterial components and TLRs (also mostly TLR2 and TLR4) (26,27). Thus, it seems most probable that the mechanism involves interactions with TLR2 and TLR4.…”

Natural Killer Cells: A Coherent Model for Their Functional Role in <b><i>Mycobacterium tuberculosis</i></b> Infection

“…It is now increasingly evident that direct sensing of microbial pathogens may represent a previously unappreciated mechanism of NK cell participation to the first line of defence against infectious agents. NK cell receptors potentially involved in the direct recognition of microbial ligands are numerous and include several members of the TLR family [18,20,21,22,23,24,25], intracellular receptors like NOD2 [26] or members of the NCR family [21,27,28,29,30,31,32,33,34,35,36,37] (table 1). …”