Human lymphocyte antigen (HLA) class I proteins of the major histocompatibility complex are largely dependent for expression on small peptides supplied to them by transporter associated with antigen processing (TAP) protein. An inherited human deficiency in the TAP transporter was identified in two siblings suffering from recurrent respiratory bacterial infections. The expression on the cell surface of class I proteins was very low, whereas that of CD1a was normal, and the cytotoxicity of natural killer cells was affected. In addition, CD8+ alpha beta T cells were present in low but significant numbers and were cytotoxic in the most severely affected sibling, who also showed an increase in CD4+CD8+ T cells and gamma delta T cells.

In this paper we describe the function and phenotype of natural killer (NK) lymphocytes from HLA class I–deficient patients. These cells are, as has been previously reported, unable to lyse HLA class I− K562 cells, but are able to perform antibody-dependent cellular cytotoxicity (ADCC), although with lower efficiency as compared to NK cells from normal individuals. Transporter associated to antigen processing (TAP)− NK cells proliferate when cultured in the presence of lymphoblastoid B cells (B-LCs) and interleukin 2 and develop a spectrum of cytotoxicity similar to that of activated normal NK cells. Importantly, activation of the TAP− NK cells induces strong cytotoxicity to autologous B-LCs. Analysis of the phenotype of circulating TAP− NK lymphocytes showed them to display a normal diverse repertoire of HLA class I–specific NK receptors. These receptors were expressed at normal levels, apart from the CD94–NKG2A complex, which appeared to be overexpressed. This latter finding could reflect an adaptation to the low expression of HLA class I molecules. Finally, functional analyses indicated that the inhibitory receptors in TAP− individuals can transduce inhibitory signals. Our results suggest that in vivo, the NK cells of TAP− patients could participate in immune defense, at least through ADCC, but upon activation, may be involved in autoimmune processes.

Human leukocyte antigen (HLA) class I deficiency is a rare disease with remarkable clinical and biological heterogeneity. The spectrum of possible manifestations extends from the complete absence of symptoms to life-threatening disease conditions. It is usually diagnosed when HLA class I serological typing is unsuccessful; flow cytometric studies then reveal a severe reduction in the cell surface expression of HLA class I molecules (90-99% reduction compared to normal cells). In most cases to date, this low expression is due to a homozygous inactivating mutation in one of the two subunits of the transporter associated with antigen processing (TAP), critically involved in the peptide loading of HLA class I molecules. Although asymptomatic cases have been described, TAP deficiencies are usually characterized by chronic bacterial infections of the upper and lower airways, evolving to bronchiectasis, and in half of the cases, also skin ulcers with features of a chronic granulomatous inflammation. Despite the defect in HLA class-I-mediated presentation of viral antigens to cytotoxic T cells, the patients do not suffer from severe viral infections, presumably because of other efficient antiviral defence mechanisms such as antibodies, non-HLA-class-I-restricted cytotoxic effector cells and CD8+ T-cell responses to TAP-independent antigens. Treatment is at present exclusively symptomatic, and should particularly focus on the prevention of bronchiectasis, which requires early detection.

IntroductionThe peptide transporter-associated antigen processing (TAP) 1,2 is a heterodimer (formed by TAP-1 and TAP-2 subunits) that imports into the lumen of the endoplasmic reticulum the peptides required for a correct assembly of HLA class I molecules. Thus, cells derived from patients displaying defective expression of either of the TAP subunits are characterized by a strong reduction of mature HLA class I molecules at the cell surface. 3 It is well known that impaired HLA class I expression renders target cells susceptible to NK-mediated cytotoxicity. 4-9 Therefore, in patients with TAP deficiency, NK-mediated autoimmune reactions could occur unless unknown fail-safe mechanisms prevent an attack against autologous normal cells expressing insufficient amounts of HLA class I molecules. In agreement with this concept, freshly isolated TAP2 Ϫ/Ϫ NK cells were unable to kill autologous, HLA class I-negative, B-lymphoblastoid cell lines (B-LCLs). 10 However, this tolerance may be broken in cases of inflammation. Indeed TAP Ϫ/Ϫ patients have been reported to have type 1 bare lymphocyte syndrome that is accompanied in childhood by sinusitis and recurrent bronchitis and in adulthood by chronic lung inflammation and bronchiectasia. 3,10 In a recent report, some TAP-deficient adult patients have been described with necrotizing granulomatous lesions in the upper respiratory tract and in the skin, with infiltrating, activated NK or T cell receptor ␥␦ ϩ cells. 11 Thus, at least in these patients, a sustained activation of NK cells, which is likely to occur in the context of recurrent infections and chronic inflammation, may lead to the disruption of self-tolerance by NK cells and, consequently, to autoimmune manifestations. In this context, after culture in the presence of interleukin (IL)-2, TAP2 Ϫ/Ϫ NK cells have been reported to acquire the ability to kill autologous Epstein-Barr virus (EBV)-transformed B-LCLs 10 or autologous fibroblasts. 12 On the other hand, though some evidence exists for the occurrence of autoimmune phenomena, it is conceivable that TAP Ϫ/Ϫ NK cells adapt to the surrounding HLA class I-negative microenvironment to avoid inappropriate attacks on otherwise normal cells. A possible mechanism that could allow TAP Ϫ/Ϫ NK cells to spare autologous normal cells would be based on the defective expression of one or another NK cell-triggering receptor.In this context, although NK cells from TAP2 Ϫ/Ϫ patients have been shown to express a normally diversified repertoire of HLA class I-specific KIRs, 10 no data are available on the expression and