Bridging Innate NK Cell Functions with Adaptive Immunity
Killer Ig-like receptors (KIRs) are major human NK receptors displaying either inhibitory or activating functions which recognize allotypic determinants of HLA-class I molecules. Surprisingly, NK cell treatment with CpG-ODN (TLR9 ligands) results in selective down-modulation of KIR3DL2, its co-internalization with CpG-ODN and its translocation to TLR9-rich early endosomes. This novel KIR-associated function may offer clues to better understand the possible role of certain KIRs and also emphasizes the involvement of NK cells in the course of microbial infections. NK cells are involved not only in innate immune responses against viruses and tumors but also participate in the complex network of cell-to cell interaction that leads to the development of adaptive immune responses. In this context the interaction of NK cells with DC appears to play a crucial role in the acquisition of CCR7, a chemokine receptor that enables NK cells to migrate towards lymph nodes in response to CCL19 and/or CCL21. Analysis of NK cell clones revealed that KIR-mismatched but not KIR-matched NK cells acquire CCR7. These data have important implications in haploidentical haematopoietic stem cell transplantation (HSCT), in which KIR-mismatched NK cells may acquire the ability to migrate to secondary lymphoid compartments (SLCs), where they can kill recipient’s antigen presenting cells (APCs) and T cells thus preventing graft versus host (and host vs. graft) reactions.
KeywordsNatural Killer Natural Killer Cell Human Natural Killer Cell Natural Killer Cell Function Natural Killer Cell Subset
This work was supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.): MFAG project n. 6383 (S.S.) and IG project n. 10643 (A.M.); Istituto Superiore di Sanità (I.S.S.), agreement n. 40G.41; Ministero della Sanità, Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica e Tecnologica (MIUR-PRIN 2006/project 2006061378_003; MIUR-FIRB 2003 project RBLA039LSF_001) and Progetto di Ricerca di Ateneo 2008 dell’Università di Genova, project E.M.
- 14.Moretta A, Vitale M, Bottino C et al (1993) P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J Exp Med 178:597–604PubMedCrossRefGoogle Scholar
- 17.Biassoni R, Cantoni C, Falco M et al (1996) The human leukocyte antigen (HLA)-C-specific “activatory” or “inhibitory” natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions. J Exp Med 183:645–650PubMedCrossRefGoogle Scholar
- 22.Bottino C, Sivori S, Vitale M et al (1996) A novel surface molecule homologous to the p58/p50 family of receptors is selectively expressed on a subset of human natural killer cells and induces both triggering of cell functions and proliferation. Eur J Immunol 26:1816–1824PubMedCrossRefGoogle Scholar
- 28.Pende D, Biassoni R, Cantoni C et al (1996) The natural killer cell receptor specific for HLA-A allotypes: a novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140-kD disulphide-linked dimer. J Exp Med 184:505–518PubMedCrossRefGoogle Scholar
- 37.Sivori S, Falco M, Carlomagno S et al. (2010) A novel KIR-associated function: evidence that CpG DNA uptake and shuttling to early endosomes is mediated by KIR3DL2. Blood 116:1637–1647Google Scholar
- 65.Moretta A, Bottino C, Pende D et al (1990) Identification of four subsets of human CD3-CD16+ natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition. J Exp Med 172:1589–1598PubMedCrossRefGoogle Scholar
- 67.Pende D, Marcenaro S, Falco M et al (2009) Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haplo-identical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. Blood 113:3119–3129PubMedCrossRefGoogle Scholar