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1.
Modeling the MHC class I pathway by combining predictions of proteasomal cleavage,TAP transport and MHC class I binding 总被引:7,自引:0,他引:7
Tenzer S Peters B Bulik S Schoor O Lemmel C Schatz MM Kloetzel PM Rammensee HG Schild H Holzhütter HG 《Cellular and molecular life sciences : CMLS》2005,62(9):1025-1037
Epitopes presented by major histocompatibility complex (MHC) class I molecules are selected by a multi-step process. Here we present the first computational prediction of this process based on in vitro experiments characterizing proteasomal cleavage, transport by the transporter associated with antigen processing (TAP) and MHC class I binding. Our novel prediction method for proteasomal cleavages outperforms existing methods when tested on in vitro cleavage data. The analysis of our predictions for a new dataset consisting of 390 endogenously processed MHC class I ligands from cells with known proteasome composition shows that the immunological advantage of switching from constitutive to immunoproteasomes is mainly to suppress the creation of peptides in the cytosol that TAP cannot transport. Furthermore, we show that proteasomes are unlikely to generate MHC class I ligands with a C-terminal lysine residue, suggesting processing of these ligands by a different protease that may be tripeptidyl-peptidase II (TPPII).Received 26 November 2004; received after revision 4 February 2005; accepted 4 March 2005S. Tenzer and B. Peters contributed equally to this work. 相似文献
2.
Evolutionary and functional perspectives of the major histocompatibility complex class I antigen-processing machinery 总被引:1,自引:0,他引:1
Paulsson KM 《Cellular and molecular life sciences : CMLS》2004,61(19-20):2446-2460
Major histocompatibility complex (MHC) class I molecules present antigenic peptides to CD8+ T cells, providing the basis for immune recognition of pathogen-infected cells. Peptides generated mainly by proteasomes in the cytosol are transported into the lumen of the endoplasmic reticulum by transporters associated with antigen processing (TAP). The maturation of MHC class I molecules is controlled by a number of accessory proteins and chaperones that are to a varying degree dedicated to the assembly of MHC class I. Several newly characterised proteins have been demonstrated to play important roles in this process. This review focuses on the functional relationship and evolutionary history of the antigen-processing machinery (APM) components and MHC class I itself. These are of great interest for further elucidating the origin of the immune system and understanding the mechanisms of antigen presentation and immunology in general. 相似文献
3.
Chemali M Radtke K Desjardins M English L 《Cellular and molecular life sciences : CMLS》2011,68(9):1533-1541
The classical view that endogenous antigens are processed by the proteasome and loaded on MHC class I molecules in the endoplasmic
reticulum, while exogenous antigens taken up by endocytosis or phagocytosis are degraded and loaded on MHC class II in lysosome-derived
organelles, has evolved along with the improvement of our understanding of the cell biology of antigen-presenting cells. In
recent years, evidence for alternative presentation pathways has emerged. Exogenous antigens can be processed by the proteasome
and loaded on MHC class I through a pathway called cross-presentation. Moreover, endogenous antigens can be targeted to lytic
organelles for presentation on MHC class II through autophagy, a highly conserved cellular process of self-eating. Recent
evidence indicates that the vacuolar degradation of endogenous antigens is also beneficial for presentation on MHC class I
molecules. This review focuses on how various forms of autophagy participate to presentation of these antigens on MHC class
I. 相似文献
4.
Effectiveness of immune surveillance of intracellular viruses and bacteria depends upon a functioning antigen presentation
pathway that allows infected cells to reveal the presence of an intracellular pathogen. The antigen presentation pathway uses
virtually all endogenous polypeptides as a source to produce antigenic peptides that are eventually chaperoned to the cell
surface by MHC class I molecules. Intriguingly, MHC I molecules present peptides encoded not only in the primary open reading
frames but also those encoded in alternate reading frames. Here, we review recent studies on the generation of cryptic pMHC
I. We focus on the immunological significance of cryptic pMHC I, and the novel translational mechanisms that allow production
of these antigenic peptides from unconventional sources. 相似文献
5.
It has been 15 years since we proposed the defective ribosomal product (DRiP) hypothesis to explain the rapid presentation
of viral peptides by MHC class I molecules on the surface of infected cells. Here, we review the evidence for the contribution
of DRiPs to antigen processing, pointing to the uncertainties regarding the physical nature of DRiPs, and emphasizing recent
findings suggesting that peptide generation is a specialized process involving compartmentalized translation. 相似文献
6.
Del Val M Iborra S Ramos M Lázaro S 《Cellular and molecular life sciences : CMLS》2011,68(9):1543-1552
CD8+ T lymphocytes screen the surface of all cells in the body to detect pathogen infection or oncogenic transformation. They
recognize peptides derived from cellular proteins displayed at the plasma membrane by major histocompatibility complex (MHC)
class I molecules. Peptides are mostly by-products of cytosolic proteolytic enzymes. Peptidic ligands of MHC class I molecules
are also generated in the secretory and vesicular pathways. Features of protein substrates, of proteases and of available
MHC class I molecules for loading peptides in these compartments shape a singular collection of ligands that also contain
different, longer, and lower affinity peptides than ligands produced in the cytosol. Especially in individuals who lack the
transporters associated with antigen processing, TAP, and in infected and tumor cells where TAP is blocked, which thus have
no supply of peptides derived from the cytosol, MHC class I ligands generated in the secretory and vesicular pathways contribute
to shaping the CD8+ T lymphocyte response. 相似文献
7.
Kristi Baker Timo Rath Wayne I. Lencer Edda Fiebiger Richard S. Blumberg 《Cellular and molecular life sciences : CMLS》2013,70(8):1319-1334
IgG is a molecule that functionally combines facets of both innate and adaptive immunity and therefore bridges both arms of the immune system. On the one hand, IgG is created by adaptive immune cells, but can be generated by B cells independently of T cell help. On the other hand, once secreted, IgG can rapidly deliver antigens into intracellular processing pathways, which enable efficient priming of T cell responses towards epitopes from the cognate antigen initially bound by the IgG. While this process has long been known to participate in CD4+ T cell activation, IgG-mediated delivery of exogenous antigens into a major histocompatibility complex (MHC) class I processing pathway has received less attention. The coordinated engagement of IgG with IgG receptors expressed on the cell-surface (FcγR) and within the endolysosomal system (FcRn) is a highly potent means to deliver antigen into processing pathways that promote cross-presentation of MHC class I and presentation of MHC class II-restricted epitopes within the same dendritic cell. This review focuses on the mechanisms by which IgG-containing immune complexes mediate such cross-presentation and the implications that this understanding has for manipulation of immune-mediated diseases that depend upon or are due to the activities of CD8+ T cells. 相似文献
8.
Ebstein F Kloetzel PM Krüger E Seifert U 《Cellular and molecular life sciences : CMLS》2012,69(15):2543-2558
The proteasome is a multi-catalytic protein complex whose primary function is the degradation of abnormal or foreign proteins. Upon exposure of cells to interferons (IFNs), the β1i/LMP2, β2i/MECL-1, and β5i/LMP7 subunits are induced and incorporated into newly synthesized immunoproteasomes (IP), which are thought to function solely as critical players in the optimization of the CD8(+) T-cell response. However, the observation that IP are present in several non-immune tissues under normal conditions and/or following pathological events militates against the view that its role is limited to MHC class I presentation. In support of this concept, the recent use of genetic models deficient for β1i/LMP2, β2i/MECL-1, or β5i/LMP7 has uncovered unanticipated functions for IP in innate immunity and non-immune processes. Herein, we review recent data in an attempt to clarify the role of IP beyond MHC class I epitope presentation with emphasis on its involvement in the regulation of protein homeostasis, cell proliferation, and cytokine gene expression. 相似文献
9.
S. K. Pierce 《Cellular and molecular life sciences : CMLS》1994,50(11-12):1026-1030
Helper T lymphocytes recognize peptide fragments of antigen bound to Major Histocompatibility Complex (MHC) class II molecules on the surfaces of antigen presenting cells (APC). Antigen processing involves internalization of the antigen into an acidic compartment where the antigen is degraded and the resulting peptide fragments of the antigen are bound to MHC class II molecules and the complexes subsequently displayed at the APC surface. Thus, antigen processing represents a complex, intracellular assembly process which may, like many intracellular protein folding and assembly processes, require the function of molecular chaperones. This contribution focuses on the evidence which suggests that members of the heat shock protein family of molecular chaperones play a role in this pathway. 相似文献
10.
The macromolecular peptide-loading complex in MHC class I-dependent antigen presentation 总被引:5,自引:1,他引:4
A challenging task for the adaptive immune system of vertebrates is to identify and eliminate intracellular antigens. Therefore
a highly specialized antigen presentation machinery has evolved to display fragments of newly synthesized proteins to effector
cells of the immune system at the cell surface. After proteasomal degradation of unwanted proteins or defective ribosome products,
resulting peptides are translocated into the endoplasmic reticulum by the transporter associated with antigen processing and
loaded onto major histocompatibility complex (MHC) class I molecules. Peptide-MHC I complexes are transported via the secretory
pathway to the cell surface where they are then inspected by cytotoxic T lymphocytes, which can trigger an immune response.
This review summarizes the current view of the intracellular machinery of antigen processing and of viral immune escape mechanisms
to circumvent destruction by the host.
Received 4 October 2005; received after revision 19 November 2005; accepted 24 November 2005 相似文献
11.
Pietersz GA Apostolopoulos V McKenzie IF 《Cellular and molecular life sciences : CMLS》2000,57(2):290-310
Tumor immunotherapy is currently receiving close scrutiny. However, with the identification of tumor antigens and their production by recombinant means, the use of cytokines and knowledge of major histocompatibility complex (MHC) class I and class II presentation has provided ample reagents for use and clear indications of how they should be used. At this time, much attention is focused on using peptides to be presented by MHC class I molecules to both induce and be targets for CD8+ cytolytic T cells. Many peptides generated endogenously or given exogenously can enter the class I pathway, but a number of other methods of entering this pathway are also known and are discussed in detail herein. While the review concentrates on inducing cytotoxic T cells (CTLs), it is becoming increasingly apparent that other modes of immunotherapy would be desirable, such as class II presentation to induce increased helper activity (for CTL), but also activating macrophages to be effective against tumor cells. 相似文献
12.
13.
Hulpke S Tomioka M Kremmer E Ueda K Abele R Tampé R 《Cellular and molecular life sciences : CMLS》2012,69(19):3317-3327
The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD(0), which is correctly targeted to and inserted into the ER membrane. In the absence of coreTAP, each TMD(0) recruits tapasin in a 1:1 stoichiometry. Although the TMD(0)s lack known ER retention/retrieval signals, they are localized to the ER membrane even in tapasin-deficient cells. We conclude that the TMD(0)s of TAP form autonomous interaction hubs linking antigen translocation into the ER with peptide loading onto MHC I, hence ensuring a major function in the integrity of the antigen-processing machinery. 相似文献
14.
The role of the proteasome in the generation of MHC class I ligands and immune responses 总被引:2,自引:2,他引:0
The ubiquitin–proteasome system (UPS) degrades intracellular proteins into peptide fragments that can be presented by major
histocompatibility complex (MHC) class I molecules. While the UPS is functional in all mammalian cells, its subunit composition
differs depending on cell type and stimuli received. Thus, cells of the hematopoietic lineage and cells exposed to (pro)inflammatory
cytokines express three proteasome immunosubunits, which form the catalytic centers of immunoproteasomes, and the proteasome
activator PA28. Cortical thymic epithelial cells express a thymus-specific proteasome subunit that induces the assembly of
thymoproteasomes. We here review new developments regarding the role of these different proteasome components in MHC class
I antigen processing, T cell repertoire selection and CD8 T cell responses. We further discuss recently discovered functions
of proteasomes in peptide splicing, lymphocyte survival and the regulation of cytokine production and inflammatory responses. 相似文献
15.
Dick TP 《Cellular and molecular life sciences : CMLS》2004,61(5):547-556
Assembly of functional major histocompatibility complex (MHC) class I peptide complexes within the endoplasmic reticulum is critically important for the development of an adaptive immune response. The highly regulated loading of peptides onto MHC class I molecules is controlled by a multi-component chaperone system called the MHC class I peptide loading complex. The recent identification of the thioredoxin family member ERp57 as a component of the loading complex led to an interesting question: Why is there a thiol-disulfide oxidoreductase inside a complex dedicated to inserting peptides into a receptor binding site? Most recently, specific ERp57-mediated disulfide bond rearrangements have been identified inside the loading complex. What these biochemical events mean for the peptide loading process remains a matter of conjecture. While several important questions wait to be answered, this review intends to summarize our current view of the oxidative folding of MHC class I molecules and addresses the question of how the receptor ligand interaction might be regulated by thiol-based redox reactions. 相似文献
16.
17.
The processing and presentation of endogenous and exogenous antigen by Schwann cells in vitro 总被引:1,自引:0,他引:1
Lilje O 《Cellular and molecular life sciences : CMLS》2002,59(12):2191-2198
The expression of major histocomatibility complex class II in vitro and in vivo by Schwann cells indicates a potential facultative
role of Schwann cells in the presentation of antigen to neuritogenic T cells during inflammatory demyelinating neuropathies.
Using a T cell proliferation assay, this study demonstrated that processing and presentation of endogenous and exogenous antigen
by Schwann cells influences T cell proliferation. Statistical analysis of proliferation and its relation to processing and
presentation of antigen by Schwann cells had not been previously addressed. Different combinations of factors including treatment
of cultures (untreated, irradiated or fixed), concentration of exogenous antigen (0 or 40 μmg/ml), the presence of interferon-γ
and the timing of exogenous antigen addition influence the proliferation P2-specific, non-mammalian protein ovalbumin-specific T cell lines and naive T cells.
Received 25 July 2002; received after revision 9 September 2002; accepted 7 October 2002 相似文献
18.
Siobhán C. Cowley 《Cellular and molecular life sciences : CMLS》2014,71(24):4831-4840
Mucosa-associated invariant T (MAIT) cells are a unique population of innate T cells that are abundant in humans. These cells possess an evolutionarily conserved invariant T cell receptor α chain restricted by the nonpolymorphic class Ib major histocompatibility (MHC) molecule, MHC class I-related protein (MR1). The recent discovery that MAIT cells are activated by MR1-bound riboflavin metabolite derivatives distinguishes MAIT cells from all other αβ T cells in the immune system. Since mammals lack the capacity to synthesize riboflavin, intermediates from the riboflavin biosynthetic pathway are distinct microbial molecular patterns that provide a unique signal to the immune system. Multiple lines of evidence suggest that MAIT cells, which produce important cytokines such as IFN-γ, TNF, and IL-17A, have the potential to influence immune responses to a broad range of pathogens. Here we will discuss our current understanding of MAIT cell biology and their role in pathogen defense. 相似文献
19.
van Endert P 《Cellular and molecular life sciences : CMLS》2011,68(9):1553-1567
Peptide ligands presented by MHC class I molecules are produced by intracellular proteolysis, which often involves multiple
steps. Initial antigen degradation seems to rely almost invariably on the proteasome, although tripeptidyl peptidase II (TPP
II) and insulin-degrading enzyme (IDE) may be able to substitute for the proteasome in rare cases. Recent evidence suggests
that the net effect of cytosolic aminopeptidases is destruction of potential class I ligands, although a positive role in
selected cases has been documented. This may apply particularly to the trimming of long precursors by TPP II. In contrast,
trimming of ligand precursors in the endoplasmic reticulum is essential for the generation of suitable peptides and has a
substantial impact on the repertoire of ligands presented. Trimming by the ER aminopeptidase (ERAP) enzymes most likely acts
on free precursors and is adapted to the needs of class I molecules by way of a molecular ruler mechanism. Trimming by ERAP
enzymes also occurs for cross-presented ligands, which can alternatively be processed in a special endosomal compartment by
insulin-regulated aminopeptidase. 相似文献
20.
M. L. Rose 《Cellular and molecular life sciences : CMLS》1998,54(9):965-978
The immunological properties of human endothelial cells suggest they perform a pivotal role in acute and chronic rejection
following solid organ transplantation. In this review the basic features of acute and chronic rejection are described as are
the cellular and molecular requirements for antigen presentation. Traditionally, antigen-presenting cells are considered to
be bone marrow-derived cells. However, these conclusions have been derived from rodent models of allograft rejection where
bone marrow-derived passenger leukocytes are the only source of donor major histocompatibility complex (MHC) class II in the
grafted organ. In contrast, in humans, virtually all the microvascular and small vessel endothelial cells are ‘constitutively’
positive for MHC class II antigens. The phenotypic properties of human endothelial cells, their response to cytokines and
their ability to stimulate resting T cells are described. Unlike bone marrow-derived antigen presenting cells (APCs), which
utilise B7/CD28 interactions, human endothelial cells utilise lymphocyte function antigen 3 (LFA3)/CD2 pathways to stimulate
T cells. They activate a CD45RO + B7-independent subpopulation of T cells. Their effect on allogeneic T cells is compared
with other non-bone marrow-derived cells such as fibroblasts, epithelial cells and smooth muscle cells, which are unable to
stimulate resting T cells. Evidence is presented suggesting that release of MHC and non-human leukocyte antigens (HLA) from
endothelial cells stimulates an alloantibody and autoimmune response leading to chronic rejection.
Received 30 March 1998; received after revision 4 May 1998; accepted 4 May 1998 相似文献