Article

Homozygous human TAP peptide transporter mutation in HLA class I deficiency. Science

University of Strasbourg, Strasburg, Alsace, France
Science (Impact Factor: 31.48). 08/1994; 265(5169):237-41. DOI: 10.1126/science.7517574
Source: PubMed

ABSTRACT 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.

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Available from: Henri de la Salle, Apr 27, 2015
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    • "only a moderate number of cases have been reported worldwide [60]. "
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    • "only a moderate number of cases have been reported worldwide [60]. The three functional modules of the TAP complex are discussed below. "
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    ABSTRACT: Background: ABC transporters ubiquitously found in all kingdoms of life move a broad range of solutes across membranes. Crystal structures of four distinct types of ABC transport systems have been solved, shedding light on different conformational states within the transport process. Briefly, ATP-dependent flipping between inward- and outward-facing conformations allows directional transport of various solutes. Scope of review: The heterodimeric transporter associated with antigen processing TAP1/2 (ABCB2/3) is a crucial element of the adaptive immune system. The ABC transport complex shuttles proteasomal degradation products into the endoplasmic reticulum. These antigenic peptides are loaded onto major histocompatibility complex class I molecules and presented on the cell surface. We detail the functional modules of TAP, its ATPase and transport cycle, and its interaction with and modulation by other cellular components. In particular, we emphasize how viral factors inhibit TAP activity and thereby prevent detection of the infected host cell by cytotoxic T-cells. Major conclusions: Merging functional details on TAP with structural insights from related ABC transporters refines the understanding of solute transport. Although human ABC transporters are extremely diverse, they still may employ conceptually related transport mechanisms. Appropriately, we delineate a working model of the transport cycle and how viral factors arrest TAP in distinct conformations. General significance: Deciphering the transport cycle of human ABC proteins is the major issue in the field. The defined peptidic substrate, various inhibitory viral factors, and its role in adaptive immunity provide unique tools for the investigation of TAP, making it an ideal model system for ABC transporters in general. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins. (C) 2014 Elsevier B.V. All tights reserved.
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    • "Indeed, an inefficient MHC transport leads to severe combined immunodeficiency as in patients with Bare Lymphocyte Syndrome type I. This disease can be caused by mutation in the TAP1, TAP2, or TAPBP genes, all leading to inefficient peptide/class I MHC transport and ultimately decreased cell surface expression (Salle de la et al., 1994). Hampering the transport of peptide/MHC complexes also plays a major role in viral infections. "
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    ABSTRACT: Cross-presentation of endocytosed antigen as peptide/class I major histocompatibility complex complexes plays a central role in the elicitation of CD8(+) T cell clones that mediate anti-viral and anti-tumor immune responses. While it has been clear that there are specific subsets of professional antigen presenting cells capable of antigen cross-presentation, identification of mechanisms involved is still ongoing. Especially amongst dendritic cells (DC), there are specialized subsets that are highly proficient at antigen cross-presentation. We here present a focused survey on the cell biological processes in the endosomal pathway that support antigen cross-presentation. This review highlights DC-intrinsic mechanisms that facilitate the cross-presentation of endocytosed antigen, including receptor-mediated uptake, maturation-induced endosomal sorting of membrane proteins, dynamic remodeling of endosomal structures and cell surface-directed endosomal trafficking. We will conclude with the description of pathogen-induced deviation of endosomal processing, and discuss how immune evasion strategies pertaining endosomal trafficking may preclude antigen cross-presentation.
    Frontiers in Immunology 03/2012; 3:37. DOI:10.3389/fimmu.2012.00037
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