NKG2D and natural cytotoxicity receptors are involved in natural killer cell interaction with self-antigen presenting cells and stromal cells.
It is thought that human natural killer (NK) lymphocytes should not damage self-tissues due to the inhibiting signal initiated by the engagement of one or another inhibitory receptor superfamily (IRS) members with self-human histocompatibility antigen (HLA)-I. During viral infection, the low expression of self-HLA-I on infected-cells leads to a reduction of the inhibiting signal and thus NK cells kill self-cells (missing self-hypothesis). Here, we have analyzed human NK cell interaction with self-cells as antigen-presenting cells (APC) or stromal cells isolated from bone marrow or skin. Despite the expression of high levels of HLA-I, APC and stromal cells are killed by interleukin (IL)-2-activated NK cells upon lymphocyte function antigen (LFA)1-(intracellular adhesion molecule) (ICAM)1 interaction. The natural cytotoxicity receptors NKp30 and NKp46 are responsible for the delivery of lethal hit to APC, whereas NKG2D-activating receptor, the ligand of the major histocompatibility complex (MHC)-related molecule MICA, and the UL16-binding protein are involved in stromal cell killing. These events are dependent on the activation of phosphoinositol 3-kinase and consequent release of perforins and granzymes. Both bone marrow stromal cells and skin fibroblasts inhibit T cell proliferation to alloantigen or triggering through CD3/T cell receptor complex. Importantly, NK cells can revert this veto effect. Altogether, these findings support the notion that NK cells can recognize self-cells possibly affecting both APC function and interaction between lymphocytes and microenvironment leading to autoreactivity.
Poggi
Alessandro
A
Laboratory of Experimental Oncology D, National Institute for Cancer Research, c/o CBA Torre A1, Largo R. Benzi 10, 16132-Genoa, Italy. alessandro.poggi@istge.it
Prevosto
Claudia
C
Zancolli
Marta
M
Canevali
Paolo
P
Musso
Alessandra
A
Zocchi
Maria Raffaella
MR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D016923:Cell Death; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005347:Fibroblasts; D052816:Foreskin / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010641:Phenotype; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000145:classification / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology