HLA class I deficiencies due to mutations in subunit 1 of the peptide transporter TAP1.

Laboratoire des Cellules Dendritiques, INSERM CJF 94-03.
Journal of Clinical Investigation (Impact Factor: 13.77). 04/1999; 103(5):R9-R13. DOI: 10.1172/JCI5687
Source: PubMed

ABSTRACT The transporter associated with antigen processing (TAP), which is composed of two subunits (TAP1 and TAP2) that have different biochemical and functional properties, plays a key role in peptide loading and the cell surface expression of HLA class I molecules. Three cases of HLA class I deficiency have previously been shown to result from the absence of a functional TAP2 subunit. In the present study, we analyzed two cases displaying not only the typical lung syndrome of HLA class I deficiency but also skin lesions, and found these patients to be TAP1-deficient. This defect leads to unstable HLA class I molecules and their retention in the endoplasmic reticulum. However, the absence of TAP1 is compatible with life and does not seem to result in higher susceptibility to viral infections than TAP2 deficiency. This work also reveals that vasculitis is often observed in HLA class I-deficient patients.


Available from: Jean-Pierre Cazenave, Jun 11, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The transporter associated with antigen processing (TAP) is a key factor of the major histocompatibility complex (MHC) class I antigen presentation pathway. This ABC transporter translocates peptides derived mainly from proteasomal degradation from the cytosol into the ER lumen for loading onto MHC class I molecules. Manifold mechanisms have evolved to regulate TAP activity. During infection, TAP expression is upregulated by interferon-gamma. Furthermore, the assembly and stability of the transport complex is promoted by various auxiliary factors. However, tumors and viruses have developed sophisticated strategies to escape the immune surveillance by suppressing TAP function. The activity of TAP can be impaired on the transcriptional or translational level, by enhanced degradation or by inhibition of peptide translocation. In this review, we briefly summarize existing data concerning the regulation of the TAP complex.
    FEBS Letters 03/2006; 580(4):1156-63. DOI:10.1016/j.febslet.2005.11.048 · 3.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Major histocompatibility complex class I proteins, which present antigenic peptides to cytotoxic T lymphocytes at the surface of all nucleated cells, are endocytosed and destroyed rapidly once their peptide ligand has dissociated. The molecular mechanism of this cellular quality control process, which prevents rebinding of exogenous peptides and thus erroneous immune responses, is unknown. To identify the nature of the decisive step in endocytic sorting of class I molecules and its location, we have followed the removal of optimally and suboptimally peptide-loaded murine H-2Kb class I proteins from the cell surface. We find that the binding of their light chain, β2-microglobulin (β2m), protects them from endocytic destruction. Thus, the extended survival of suboptimally loaded Kb molecules at 25°C is attributed to decreased dissociation of β2m. Because all forms of Kb are constantly internalized but little β2m-receptive heavy chain is present at the cell surface, it is likely that β2m dissociation and recognition of the heavy chain for lysosomal degradation take place in an endocytic compartment.
    The FASEB Journal 03/2015; DOI:10.1096/fj.14-268094 · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peripheral blood natural killer (NK) cells from patients with transporter associated with antigen processing (TAP) deficiency are hyporesponsive. The mechanism of this defect is unknown, but the phenotype of TAP-deficient NK cells is almost normal. However, we noticed a high percentage of CD56(bright) cells among total NK cells from two patients. We further investigated TAP-deficient NK cells in these patients and compared them to NK cells from two other TAP-deficient patients with no clinical symptoms and to individuals with chronic inflammatory diseases other than TAP deficiency (chronic lung diseases or vasculitis). Peripheral blood mononuclear cells isolated from venous blood were stained with fluorochrome-conjugated antibodies and the phenotype of NK cells was analyzed by flow cytometry. In addition, (51)Chromium release assays were performed to assess the cytotoxic activity of NK cells. In the symptomatic patients, CD56(bright) NK cells represented 28% and 45%, respectively, of all NK cells (higher than in healthy donors). The patients also displayed a higher percentage of CD56(dim)CD16(-) NK cells than controls. Interestingly, this unusual NK cell subtype distribution was not found in the two asymptomatic TAP-deficient cases, but was instead present in several of the other patients. Over-expression of the inhibitory receptor CD94/NKG2A by TAP-deficient NK cells was confirmed and extended to the inhibitory receptor ILT2 (CD85j). These inhibitory receptors were not involved in regulating the cytotoxicity of TAP-deficient NK cells. We conclude that expansion of the CD56(bright) NK cell subtype in peripheral blood is not a hallmark of TAP deficiency, but can be found in other diseases as well. This might reflect a reaction of the immune system to pathologic conditions. It could be interesting to investigate the relative distribution of NK cell subsets in various respiratory and autoimmune diseases.
    PLoS ONE 02/2007; 2(10):e1033. DOI:10.1371/journal.pone.0001033 · 3.53 Impact Factor