Inefficient protection of human TAP-deficient fibroblasts from autologous NK cell-mediated lysis by cytokines inducing HLA class I expression

We studied HLA class I expression and susceptibility to lysis of activated autologous NK cells in normal and TAP-deficient fibroblasts. These cells we re cultured in the presence or absence of cytokines known to increase the s urface expression of HLA class I molecules. AII the cytokines tested (IFN-a lpha, IFN-gamma, TNF-alpha and IFN-gamma + TNF-alpha) increased the express ion of HLA class I molecules on fibroblasts after 48-h culture, but on TAP- deficient cells this expression remained very low as compared to that of no rmal cells. In the presence of IFN-alpha, IFN-gamma or IFN-gamma + TNF-alph a, normal target cells became resistant to lysis by autologous NK cells, wh ereas this effect was much less pronounced in the case of TAP-deficient fib roblasts. Addition of an anti-HLA class I mAb to fibroblasts treated with c ytokines increased lysis of normal but not of TAP-deficient cells. These re sults suggest that activated TAP-deficient NK cells are strongly cytotoxic to normal autologous cells and that these cells cannot be efficiently prote cted by cytokines inducing HLA class I expression. Thus, in human TAP defic iency, activated NK cells may contribute to the progressive lung degradatio n which characterizes the clinical course of these patients.