Anchor sequence-dependent endogenous processing of human immunodeficiency virus 1 envelope glycoprotein gp160 for CD4+ T cell recognition.

Polydefkis, Michael; Koenig, Scott; Flexner, Charles; Obah, Eugene; Gebo, Kelly A.; Chakrabarti, Sekhar; Earl, Patricia L.; Moss, Bernard; Siliciano, Robert F.

doi:10.1084/jem.171.3.875

Cited by 47 publications

(21 citation statements)

References 34 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The traditional pathway involves the endocytosis of exogenous proteins by APC. In contrast, the second pathway implicates the processing of endogenously synthesized membrane proteins (42). These membrane proteins are believed to enter endosomal compartments by internalization from the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Melanosomal Targeting Sequences from gp100 Are Essential for MHC Class II–Restricted Endogenous Epitope Presentation and Mobilization to Endosomal Compartments

Lepage

Lapointe

2006

Cancer Research

View full text Add to dashboard Cite

CD4+ T lymphocytes play an important role in CD8 + T cellmediated responses against tumors. Considering that f20% of melanomas express MHC class II, it is plausible that concomitant presentation by MHC class I and class II shapes positive (helper T cells) or negative (regulatory T cells) antitumor responses. Interestingly, gp100, a melanoma antigen, can be presented by both MHC class I and class II when expressed endogenously, suggesting that it can reach endosomal/MHC class II compartments (MIIC). Here, we showed that gp100 putative NH 2 -terminal signal sequence and the last 70 residues in COOH terminus are essential for MIIC localization and MHC class II presentation. Confocal microscopy analyses confirmed that gp100 was localized in LAMP-1 + / HLA-DR + endosomal/MIIC. Gp100 targeting sequences were characterized by deleting different sections in the COOH terminus (last 70 residues). Transfection in 293T cells, expressing MHC class I and class II molecules, revealed that specific deletions in COOH terminus resulted in decreased MHC class II presentation, without effects on class I presentation, suggesting a role in MIIC trafficking for these deleted sections. Then, we used these gp100 targeting sequences to mobilize green fluorescent protein to endosomal compartments and to allow MHC class II and class I presentation of minimal endogenous epitopes. We conclude that these specific sequences are MIIC-targeting motifs, which could be included in expression cassettes for endogenously expressed tumor or viral antigens for MHC class II and class I presentation and optimize in vivo T-cell responses or as an in vitro tool for characterization of new MHC class II epitopes.

show abstract

Section: Discussionmentioning

confidence: 99%

Melanosomal Targeting Sequences from gp100 Are Essential for MHC Class II–Restricted Endogenous Epitope Presentation and Mobilization to Endosomal Compartments

Lepage

Lapointe

2006

Cancer Research

View full text Add to dashboard Cite

show abstract

“…From the literature, there are several potential routes whereby endogenously expressed Ags might directly enter the MHC class II pathway. Some of these appear to be restricted to membrane or secreted proteins which naturally intercept nascent MHC class II molecules in the endoplasmic reticulum (13)(14)(15)(16). Others can involve cytoplasmic and even nuclear proteins being directly delivered to the endosomal MHC class II-loading compartment (18,21,(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

“…There are multiple examples where indicator Ags have been expressed endogenously within LCL cells and appear to have gained direct intracellular entry into the HLA class II-processing pathway, apparently bypassing the normal exogenous pathway in which Ag is taken up from the extracellular milieu before being processed in endo/lysosomal compartments. Many of these examples involve membrane or secreted proteins (13)(14)(15)(16) which are thought to engage immature MHC class II molecules during transit through the endoplasmic reticulum. However, others involve long-lived cytoplasmic proteins, stably expressed in cells by gene transfection, which appear to enter the endosomal compartment either by a specialized chaperonemediated route (17) or by a pathway that was blocked by 3-methyladenine (3-MA) (18), a known inhibitor of autophagy (19).…”

Section: Cd8mentioning

confidence: 99%

A Role for Intercellular Antigen Transfer in the Recognition of EBV-Transformed B Cell Lines by EBV Nuclear Antigen-Specific CD4+ T Cells

Taylor

Long

Haigh

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

The CD4+ T cell response to EBV may have an important role in controlling virus-driven B lymphoproliferation because CD4+ T cell clones to a subset of EBV nuclear Ag (EBNA) epitopes can directly recognize virus-transformed lymphoblastoid cell lines (LCLs) in vitro and inhibit their growth. In this study, we used a panel of EBNA1, 2, 3A, and 3C-specific CD4+ T cell clones to study the route whereby endogenously expressed EBNAs access the HLA class II-presentation pathway. Two sets of results spoke against a direct route of intracellular access. First, none of the clones recognized cognate Ag overexpressed in cells from vaccinia vectors but did recognize Ag fused to an endo/lysosomal targeting sequence. Second, focusing on clones with the strongest LCL recognition that were specific for EBNA2- and EBNA3C-derived epitopes LCL recognition was unaffected by inhibiting autophagy, a postulated route for intracellular Ag delivery into the HLA class II pathway in LCL cells. Subsequently, using these same epitope-specific clones, we found that Ag-negative cells with the appropriate HLA-restricting allele could be efficiently sensitized to CD4+ T cell recognition by cocultivation with Ag-positive donor lines or by exposure to donor line-conditioned culture medium. Sensitization was mediated by a high m.w. antigenic species and required active Ag processing by recipient cells. We infer that intercellular Ag transfer plays a major role in the presentation of EBNA-derived CD4 epitopes by latently infected target cells.

show abstract

“…This raises the possibility that virus-specific CD4 ϩ T cells are able to recognize infected cells directly and, if they are, could act (like CD8 ϩ T cells) as effectors in their own right. Certainly there are examples where indicator antigens have been expressed endogenously within LCLs and appear to have gained direct intracellular entry into the HLA class II processing pathway (2,20,23,34), in some way bypassing the usual means of HLA class II presentation involving uptake as exogenously acquired antigen (33). The first CD4…”

mentioning

confidence: 99%

CD4⁺T-Cell Responses to Epstein-Barr Virus (EBV) Latent-Cycle Antigens and the Recognition of EBV-Transformed Lymphoblastoid Cell Lines

Long

Haigh

Gudgeon

et al. 2005

J Virol

111

163

View full text Add to dashboard Cite

There is considerable interest in the potential of Epstein-Barr virus (EBV) latent antigen-specific CD4؉ T cells to act as direct effectors controlling EBV-induced B lymphoproliferations. Such activity would require direct CD4؉ T-cell recognition of latently infected cells through epitopes derived from endogenously expressed viral proteins and presented on the target cell surface in association with HLA class II molecules. It is therefore important to know how often these conditions are met. Here we provide CD4؉ epitope maps for four EBV nuclear antigens, EBNA1, -2, -3A, and -3C, and establish CD4 ؉ T-cell clones against 12 representative epitopes. For each epitope we identify the relevant HLA class II restricting allele and determine the efficiency with which epitope-specific effectors recognize the autologous EBV-transformed B-lymphoblastoid cell line (LCL). The level of recognition measured by gamma interferon release was consistent among clones to the same epitope but varied between epitopes, with values ranging from 0 to 35% of the maximum seen against the epitope peptide-loaded LCL. These epitope-specific differences, also apparent in short-term cytotoxicity and longer-term outgrowth assays on LCL targets, did not relate to the identity of the source antigen and could not be explained by the different functional avidities of the CD4 ؉ clones; rather, they appeared to reflect different levels of epitope display at the LCL surface. Thus, while CD4 ؉ T-cell responses are detectable against many epitopes in EBV latent proteins, only a minority of these responses are likely to have therapeutic potential as effectors directly recognizing latently infected target cells.

show abstract

Anchor sequence-dependent endogenous processing of human immunodeficiency virus 1 envelope glycoprotein gp160 for CD4+ T cell recognition.

Cited by 47 publications

References 34 publications

Melanosomal Targeting Sequences from gp100 Are Essential for MHC Class II–Restricted Endogenous Epitope Presentation and Mobilization to Endosomal Compartments

Melanosomal Targeting Sequences from gp100 Are Essential for MHC Class II–Restricted Endogenous Epitope Presentation and Mobilization to Endosomal Compartments

A Role for Intercellular Antigen Transfer in the Recognition of EBV-Transformed B Cell Lines by EBV Nuclear Antigen-Specific CD4+ T Cells

CD4⁺T-Cell Responses to Epstein-Barr Virus (EBV) Latent-Cycle Antigens and the Recognition of EBV-Transformed Lymphoblastoid Cell Lines

Contact Info

Product

Resources

About

Anchor sequence-dependent endogenous processing of human immunodeficiency virus 1 envelope glycoprotein gp160 for CD4+ T cell recognition.

Cited by 47 publications

References 34 publications

Melanosomal Targeting Sequences from gp100 Are Essential for MHC Class II–Restricted Endogenous Epitope Presentation and Mobilization to Endosomal Compartments

Melanosomal Targeting Sequences from gp100 Are Essential for MHC Class II–Restricted Endogenous Epitope Presentation and Mobilization to Endosomal Compartments

A Role for Intercellular Antigen Transfer in the Recognition of EBV-Transformed B Cell Lines by EBV Nuclear Antigen-Specific CD4+ T Cells

CD4+T-Cell Responses to Epstein-Barr Virus (EBV) Latent-Cycle Antigens and the Recognition of EBV-Transformed Lymphoblastoid Cell Lines

Contact Info

Product

Resources

About

CD4⁺T-Cell Responses to Epstein-Barr Virus (EBV) Latent-Cycle Antigens and the Recognition of EBV-Transformed Lymphoblastoid Cell Lines