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a Laboratory of Experimental Oncology D, National Institute for Cancer Research, Genoa, Italy b Laboratory of Tumor Immunology, San Raffaele Scientific Institute, Milan, Italy
Key Words: natural killer cells • mesenchymal stem cells • stromal cells • skin fibroblast • antigen-presenting cells • NKG2D • natural cytotoxicity receptors
Address for correspondence: Alessandro Poggi, Ph.D., M.D., Laboratory of Experimental Oncology D, National Institute for Cancer Research, c/o CBA Torre A1, Largo R. Benzi 10, 16132-Genoa, Italy. Voice: +390105737211; fax: +39010354282. alessandro.poggi{at}istge.it
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.
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