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

1999 ◽  
Vol 190 (9) ◽  
pp. 1227-1240 ◽  
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.

In Vitro Induction of Specific Cytotoxic T Lymphocytes Using Recombinant Single-Chain MHC Class I/Peptide Complexes

1998 ◽  
Vol 21 (4) ◽  
pp. 283-294 ◽  
Author(s):  
Yu-Chun Lone ◽  
Iris Motta ◽  
Estelle Mottez ◽  
Yannik Guilloux ◽  
Annick Lim ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Mhc Class I ◽  
Cytotoxic T Lymphocytes ◽  
Class I ◽  
Single Chain ◽  
Peptide Complexes ◽  
In Vitro Induction

scholarly journals The many roads to cross-presentation

2005 ◽  
Vol 202 (10) ◽  
pp. 1313-1318 ◽  
Author(s):  
Tom A.M. Groothuis ◽  
Jacques Neefjes
Keyword(s):  
Endoplasmic Reticulum ◽  
T Lymphocytes ◽  
Mhc Class I ◽  
Cytotoxic T Lymphocytes ◽  
Class I ◽  
Cross Presentation ◽  
Peptide Loading ◽  
The Many ◽  
Mhc Class I Molecules

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.

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

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1909-1914 ◽  
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.

scholarly journals Modulation of Transporter Associated with Antigen Processing (TAP)-Mediated Peptide Import into the Endoplasmic Reticulum by Flavivirus Infection

2001 ◽  
Vol 75 (12) ◽  
pp. 5663-5671 ◽  
Author(s):  
Frank Momburg ◽  
Arno Müllbacher ◽  
Mario Lobigs
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Surface Expression ◽  
Class I ◽  
Peptide Transport ◽  
Cell Surface Expression ◽  
Flavivirus Infection ◽  
Mhc Class I Molecules

ABSTRACT In contrast to many other viruses that escape the cellular immune response by downregulating major histocompatibility complex (MHC) class I molecules, flavivirus infection can upregulate their cell surface expression. Previously we have presented evidence that during flavivirus infection, peptide supply to the endoplasmic reticulum is increased (A. Müllbacher and M. Lobigs, Immunity 3:207–214, 1995). Here we show that during the early phase of infection with different flaviviruses, the transport activity of the peptide transporter associated with antigen processing (TAP) is augmented by up to 50%. TAP expression is unaltered during infection, and viral but not host macromolecular synthesis is required for enhanced peptide transport. This study is the first demonstration of transient enhancement of TAP-dependent peptide import into the lumen of the endoplasmic reticulum as a consequence of a viral infection. We suggest that the increased supply of peptides for assembly with MHC class I molecules in flavivirus-infected cells accounts for the upregulation of MHC class I cell surface expression with the biological consequence of viral evasion of natural killer cell recognition.

Induction of Survivin-Specific, HLA-A24 Restricted Cytotoxic T Lymphocytes Using an Immunodominant Peptide; In-Vitro Feasibility Study and a Clinical Trial of Survivin Peptide Vaccination.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2709-2709
Author(s):  
Masahiro Ogasawara ◽  
Misato Kikuchi ◽  
Satoru Kimura ◽  
Koichiro Kobayashi ◽  
Takayoshi Miyazono ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Lymphocytes ◽  
Healthy Volunteers ◽  
Cytotoxic T Lymphocytes ◽  
Feasibility Study ◽  
Hla Class I ◽  
Class I ◽  
Peptide Vaccination ◽  
Lymphoma Cells

Abstract Survivin, a member of the inhibitors of the apoptosis family, is overexpressed frequently in a variety of cancers and hematological malignancies, but not in normal tissues. Murine in vivo and human in vitro studies have suggested that immunotherapy of cancer patients using survivin peptide might be feasible. In the present study, we examined whether HLA-A24 restricted cytotoxic T lymphocytes (CTL) which recognize survivin peptide can be generated from peripheral blood of lymphoma patients. HLA-A24 positive four lymphoma patients and two healthy volunteers were enrolled. Three immunodominant 9-mer candidate peptides (2B, 3A, 3B) were selected on the basis of anchoring motif of peptide binding to HLA-A24 molecule. CD8 T cells from the patients and healthy volunteers were stimulated several times with autologous monocyte-derived dendritic cells pulsed with survivin or control HIV peptides and tested for peptide-specific cytotoxicity by an LDH-release assay. CTL generated with survivin 2B peptide lysed autologous monocytes pulsed with a relevant peptide. However, other survivin peptides did not elicit CTL response. Non-pulsed or HIV peptide-pulsed monocytes were not lysed. On the other hand, CTL generated with HIV peptide only lysed HIV peptide-pulsed monocytes. CTL did not lyse allogeneic monocytes regardless of the peptide pulse. Cytotoxic activity was inhibited by the pretreatment of target cells by anti-HLA class I, not by anti-HLA-DR monoclonal antibody, indicating that the lysis was HLA class I (A24) restricted. These cells did not lyse Daudi and K562, excluding the involvement of LAK or NK activity. Importantly, these survivin peptide-specific CTL showed cytotoxicity to the patient’s lymphoma cells and HLA-A24 positive lymphoma cells. Based on these preclinical data, we have just started a pilot clinical study to examine the safety and the efficacy of peptide vaccination to relapsed, chemotherapy-resistant malignant lymphoma patients who are HLA-A24 and survivin positive. A 46-year old male patient with diffuse large B-cell lymphoma has just completed two courses of four vaccinations at two-week intervals with survivin 2B peptide (1 μg subcutaneously) in an incomplete Freund’s adjuvant (Montanide ISA-51, SEPPIC Co. France). We observed a marked decrease in the size of extra-nodular surface and cervical lymphnodes following vaccinations without serious adverse events. Immunological evaluations using HLA-tetramer and T cell receptor clonality assays revealed an increase in survivin-specific CTL frequency after vaccinations. The in-vitro feasibility study and pilot clinical trial indicate that a vaccination with a survivin peptide is safe and might be a promising novel strategy for the treatment of lymphoma patients.

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