In vitro induction of naive cytotoxic T lymphocytes with complexes of peptide and recombinant MHC class I molecules coated onto beads: role of TCR/ligand density

Cross-presentation of extracellular antigens by MHC class I molecules is required for priming cytotoxic T lymphocytes (CTLs) at locations remote from the site of infection. Various mechanisms have been proposed to explain cross-presentation. One such mechanism involves the fusion of the endoplasmic reticulum (ER) with the endosomal-phagosomal system, in which the machinery required for peptide loading of MHC class I molecules is introduced directly into the phagosome. Here, we discuss the evidence for and against the ER-phagosome concept as well as other possible mechanisms of cross-presentation.

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Human Transporters Associated with Antigen Processing (Taps) Select Epitope Precursor Peptides for Processing in the Endoplasmic Reticulum and Presentation to T Cells

Journal of Experimental Medicine ◽

10.1084/jem.190.9.1227 ◽

1999 ◽

Vol 190 (9) ◽

pp. 1227-1240 ◽

Cited By ~ 68

Author(s):

Grégoire Lauvau ◽

Kazuhiro Kakimi ◽

Gabriele Niedermann ◽

Marina Ostankovitch ◽

Patricia Yotnda ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

T Lymphocytes ◽

Antigen Presentation ◽

Mhc Class I ◽

Cytotoxic T Lymphocytes ◽

Antigen Processing ◽

High Efficiency ◽

Class I ◽

Aminopeptidase Activity

Antigen presentation by major histocompatibility complex (MHC) class I molecules requires peptide supply by the transporters associated with antigen processing (TAPs), which select substrates in a species- and, in the rat, allele-specific manner. Conflicts between TAPs and MHC preferences for COOH-terminal peptide residues in rodent cells strongly reduce the efficiency of MHC class I antigen presentation. Although human TAP is relatively permissive, some peptide ligands for human histocompatibility leukocyte antigen class I molecules are known to possess very low TAP affinities; the significance of these in vitro findings for cellular antigen presentation is not known. We studied two naturally immunodominant viral epitopes presented by HLA-A2 that display very low affinities for human TAP. Low TAP affinities preclude minimal epitope access to the endoplasmic reticulum (ER) and assembly with HLA-A2 in vitro, as well as presentation by minigene-expressing cells to cytotoxic T lymphocytes. However, NH2-terminally but not COOH-terminally extended epitope variants with higher TAP affinities assemble in vitro and are presented to cytotoxic T lymphocytes with high efficiency. Thus, human TAP can influence epitope selection and restrict access to the ER to epitope precursors. Analysis of TAP affinities of a panel of viral epitopes suggests that TAP selection of precursors may be a common phenomenon for HLA-A2–presented epitopes. We also analyzed HLA-A2–eluted peptides from minigene-expressing cells and show that an NH2-terminally extended variant with low A2 binding affinity undergoes ER processing, whereas another with high affinity is presented unmodified. Therefore, the previously reported aminopeptidase activity in the ER can also act on TAP-translocated peptides.

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Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro

Cell ◽

10.1016/0092-8674(90)90020-f ◽

1990 ◽

Vol 62 (3) ◽

pp. 563-567 ◽

Cited By ~ 275

Author(s):

Ton N.M. Schumacher ◽

Marie-Thérèse Heemels ◽

Jacques J. Neefjes ◽

W.Martin Kast ◽

Cees J.M. Melief ◽

...

Keyword(s):

Mhc Class I ◽

Class I ◽

Intact Cells ◽

Direct Binding ◽

Mhc Class I Molecules

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MHC Class I Molecules Exacerbate Viral Infection by Disrupting Type I Interferon Signaling

Journal of Immunology Research ◽

10.1155/2019/5370706 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Simo Xia ◽

Yijie Tao ◽

Likun Cui ◽

Yizhi Yu ◽

Sheng Xu

Keyword(s):

Viral Infection ◽

Mhc Class I ◽

Class I ◽

Type I ◽

Type I Ifn ◽

Mhc I ◽

Cell Responses ◽

Innate Antiviral Immunity ◽

Mhc Class I Molecules

MHC class I molecules are key in the presentation of antigen and initiation of adaptive CD8+ T cell responses. In addition to its classical activity, MHC I may possess nonclassical functions. We have previously identified a regulatory role of MHC I in TLR signaling and antibacterial immunity. However, its role in innate antiviral immunity remains unknown. In this study, we found a reduced viral load in MHC I-deficient macrophages that was independent of type I IFN production. Mechanically, MHC I mediated viral suppression by inhibiting the type I IFN signaling pathway, which depends on SHP2. Cross-linking MHC I at the membrane increased SHP2 activation and further suppressed STAT1 phosphorylation. Therefore, our data revealed an inhibitory role of MHC I in type I IFN response to viral infection and expanded our understanding of MHC I and antigen presentation.

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Detection of major histocompatibility complex class I-restricted, HIV- specific cytotoxic T lymphocytes in the blood of infected hemophiliacs

Blood ◽

10.1182/blood.v73.7.1909.1909 ◽

1989 ◽

Vol 73 (7) ◽

pp. 1909-1914 ◽

Cited By ~ 47

Author(s):

RA Koup ◽

JL Sullivan ◽

PH Levine ◽

D Brettler ◽

A Mahr ◽

...

Keyword(s):

T Lymphocytes ◽

Mhc Class I ◽

Cytotoxic T Lymphocytes ◽

Mononuclear Cells ◽

Nk Cell ◽

Class I ◽

Gene Products ◽

Major Histocompatibility ◽

Peripheral Blood Mononuclear ◽

Hiv 1

Abstract Major histocompatibility (MHC)-restricted, human immunodeficiency virus type one (HIV-1)-specific, cytotoxic T lymphocytes (CTLs) were detected in the peripheral blood mononuclear cells (PBMCs) of HIV-1-infected individuals. Using a system of autologous B and T lymphoblastoid cell lines infected with recombinant vaccinia vectors (VVs) expressing HIV-1 gene products, we were able to detect HIV-1-specific cytolytic responses in the PBMCs of 88% of HIV-1-seropositive hemophiliac patients in the absence of in vitro stimulation. These cytolytic responses were directed against both HIV-1 envelope and gag gene products. The responses were resistant to natural killer (NK) cell depletion and were inhibited by monoclonal antibodies (MoAbs) to the T cell receptor, CD8 surface antigens, and MHC class I antigens, suggesting a classical MHC class I restricted, virus-specific CTL response.

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TAP expression level in tumor cells defines the nature and processing of MHC class I peptides for recognition by tumor-specific cytotoxic T lymphocytes

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2012.06777.x ◽

2013 ◽

Vol 1283 (1) ◽

pp. 75-80 ◽

Cited By ~ 8

Author(s):

Faten El Hage ◽

Aurélie Durgeau ◽

Fathia Mami-Chouaib

Keyword(s):

T Lymphocytes ◽

Tumor Cells ◽

Mhc Class I ◽

Cytotoxic T Lymphocytes ◽

Expression Level ◽

Class I

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The role of mutated SOD1 gene in synaptic stripping and MHC class I expression following nerve axotomy in ALS murine model

European Journal of Histochemistry ◽

10.4081/ejh.2018.2904 ◽

2018 ◽

Author(s):

Roman M. Kassa ◽

Roberta Bonafede ◽

Federico Boschi ◽

Manuela Malatesta ◽

Raffaella Mariotti

Keyword(s):

Mhc Class I ◽

Murine Model ◽

Excitatory Input ◽

Class I ◽

Facial Motoneurons ◽

Cellular Pathways ◽

First Time ◽

Lateral Sclerosis ◽

Mhc Class I Molecules

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motoneuron death. Several cellular pathways have been described to be involved in ALS pathogenesis; however, the involvement of presynaptic stripping and the related MHC class I molecules in mutant SOD1 motoneurons remains to be clarified. To this purpose, we here investigated, for the first time, the motoneurons behavior, di per seand after facial axonal injury, in terms of synaptic stripping and MHC class I expression in wild-type (Wt) mice and in a murine model of ALS, the SOD1(G93A) mice, at the presymptomatic and symptomatic stage of the disease. Concerning Wt animals, we found a reduction in synaptophysin immunoreactivity and an increase of MHC class I molecules in facial motoneurons after axotomy. In uninjured motoneurons of SOD1(G93A) mice, an altered presynaptic framework was evident, and this phenomenon increased during the disease course. The alteration in the presynaptic input is related to excitatory fibers. Moreover, after injury, a further decrease of excitatory input was not associated to an upregulation of MHC class I molecules in motoneuron soma. This study demonstrates, for the first time, that the presence of mutated SOD1 protein affects the MHC class I molecules expression, altering the presynaptic input in motoneurons. Nevertheless, a positive MHC class I immunolabeling was evident in glial cells around facial injured motoneurons, underlying an involvement of these cells in synaptic stripping. This study contributes to better understand the involvement of the mutated SOD1 protein in the vulnerability of motoneurons after damage.

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