Major histocompatibility complex class II-restricted presentation of an internally synthesized antigen displays cell-type variability and segregates from the exogenous class II and endogenous class I presentation pathways.

Loss, George E.; Elias, C G; Fields, Patrick E.; Ribaudo, Randall K.; McKisic, M D; Sant, Andrea J.

doi:10.1084/jem.178.1.73

Cited by 57 publications

(48 citation statements)

References 62 publications

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“…For example, the UV inactivation of A/PR8/34 influenza virus (PR8) or treatment of infected antigen-presenting cells (APCs) with protein synthesis inhibitors prevents the presentation of the NA79 epitope (12). Similar observations have been made for an epitope derived from influenza matrix protein 1 (24) and an epitope derived from the MHC class I H2-L d molecule (39).…”

supporting

confidence: 51%

Functional Macroautophagy Induction by Influenza A Virus without a Contribution to Major Histocompatibility Complex Class II-Restricted Presentation

Comber

Robinson

Siciliano

et al. 2011

J Virol

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Major histocompatibility complex (MHC) class II-presented peptides can be derived from both exogenous (extracellular) and endogenous (biosynthesized) sources of antigen. Although several endogenous antigenprocessing pathways have been reported, little is known about their relative contributions to global CD4؉ T cell responses against complex antigens. Using influenza virus for this purpose, we assessed the role of macroautophagy, a process in which cytosolic proteins are delivered to the lysosome by de novo vesicle formation and membrane fusion. Influenza infection triggered productive macroautophagy, and autophagy-dependent presentation was readily observed with model antigens that naturally traffic to the autophagosome. Furthermore, treatments that enhance or inhibit macroautophagy modulated the level of presentation from these model antigens. However, validated enzyme-linked immunospot (ELISpot) assays of influenza-specific CD4 ؉ T cells from infected mice using a variety of antigen-presenting cells, including primary dendritic cells, revealed no detectable macroautophagy-dependent component. In contrast, the contribution of proteasome-dependent endogenous antigen processing to the global influenza CD4؉ response was readily appreciated. The contribution of macroautophagy to the MHC class II-restricted response may vary depending upon the pathogen. The activation of CD4ϩ T cells depends upon their recognition of peptides (epitopes) associated with major histo compatibility class (MHC) class II molecules. Conventionally, peptide generation involves the degradation of exogenous (extracellular) antigens in the endosomal network by multiple mechanisms, including unfolding, reduction, and proteolytic degradation. It is now clear that epitopes derived from endogenous antigens (synthesized by the cell) also can be presented on MHC class II molecules (12,22,24,38,49,50,60,66). Indeed, endogenous antigen expression appears to be an absolute requirement for the presentation of some epitopes. For example, the UV inactivation of A/PR8/34 influenza virus (PR8) or treatment of infected antigen-presenting cells (APCs) with protein synthesis inhibitors prevents the presentation of the NA79 epitope (12). Similar observations have been made for an epitope derived from influenza matrix protein 1 (24) and an epitope derived from the MHC class I H2-L d molecule (39).Numerous studies now have demonstrated that endogenous antigens can gain access to MHC class II loading compartments via a variety of intracellular pathways (4,38,49,57,66,67). Perhaps the most straightforward route is autophagy, in which cytosolic proteins are delivered to the lysosome via several different mechanisms. Chaperone-mediated autophagy results in the delivery of cytosolic proteins directly to the lysosome based upon the recognition of a KFERQ pentapeptide motif within the target protein, and it was shown to be responsible for the presentation of an epitope derived from glutamate decarboxylase (72). Although 30% of cytosolic proteins contain this motif (70)...

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supporting

confidence: 51%

Functional Macroautophagy Induction by Influenza A Virus without a Contribution to Major Histocompatibility Complex Class II-Restricted Presentation

Comber

Robinson

Siciliano

et al. 2011

J Virol

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“…54). Although some investigators have found that TAP is not required for presentation of endogenously synthesized MHC II-restricted peptides (41,55,56), others have found that presentation is TAP dependent (57,58). It has been suggested that this discrepancy in the apparent requirement for TAP is due to differences in Ag stability, because rapidly degraded, but not long-lived cytosolic Ag requires TAP for Ag presentation (59).…”

Section: Discussionmentioning

confidence: 99%

Presentation of Endogenously Synthesized MHC Class II-Restricted Epitopes by MHC Class II Cancer Vaccines Is Independent of Transporter Associated with Ag Processing and the Proteasome

Dissanayake

Tuera

Ostrand‐Rosenberg

2005

The Journal of Immunology

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Cell-based vaccines consisting of invariant chain-negative tumor cells transfected with syngeneic MHC class II (MHC II) and costimulatory molecule genes are prophylactic and therapeutic agents for the treatment of murine primary and metastatic cancers. Vaccine efficacy is due to direct presentation of endogenously synthesized, MHC II-restricted tumor peptides to CD4+ T cells. Because the vaccine cells lack invariant chain, we have hypothesized that, unlike professional APC, the peptide-binding groove of newly synthesized MHC II molecules may be accessible to peptides, allowing newly synthesized MHC II molecules to bind peptides that have been generated in the proteasome and transported into the endoplasmic reticulum via the TAP complex. To test this hypothesis, we have compared the Ag presentation activity of multiple clones of TAP-negative and TAP-positive tumor cells transfected with I-Ak genes and the model Ag hen egg white lysozyme targeted to the endoplasmic reticulum or cytoplasm. Absence of TAP does not diminish Ag presentation of three hen egg white lysozyme epitopes. Likewise, cells treated with proteasomal and autophagy inhibitors are as effective APC as untreated cells. In contrast, drugs that block endosome function significantly inhibit Ag presentation. Coculture experiments demonstrate that the vaccine cells do not release endogenously synthesized molecules that are subsequently endocytosed and processed in endosomal compartments. Collectively, these data indicate that vaccine cell presentation of MHC II-restricted endogenously synthesized epitopes occurs via a mechanism independent of the proteasome and TAP complex, and uses a pathway that overlaps with the classical endosomal pathway for presentation of exogenously synthesized molecules.

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“…However, some endogenous Ags, those synthesized within the APC, can gain access to the MHC II presentation pathway (25). Indeed, it appears that some epitopes can be generated only through the processing of endogenous Ag (26,27). Recent studies have implicated both cytosolic proteases, including the proteasome, and endosome resident proteases in the generation of epitopes from endogenous proteins, including transmembrane proteins (28 -30).…”

Section: D4mentioning

confidence: 99%

Presentation by Recycling MHC Class II Molecules of an Influenza Hemagglutinin-Derived Epitope That Is Revealed in the Early Endosome by Acidification

Sinnathamby

Eisenlohr

2003

The Journal of Immunology

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We investigated the roles of nascent and recycling MHC class II molecules (MHC II) in the presentation of two well-defined I-Ed-restricted epitopes that are within distinct regions of the influenza virus hemagglutinin (HA) protein. The site 3 epitope (S3; residues 302–313) lies in the stalk region that unfolds in response to mild acidification, while the site 1 epitope (S1; residues 107–119) is situated in the stable globular domain. In a murine B lymphoma cell line and an I-Ed-transfected fibroblast cell line, presentation from inactivated virus of S3 is inhibited by primaquine, a compound that prevents recycling of cell surface proteins, including MHC II, while S1 presentation is unaffected. In contrast, brefeldin A, an agent that inhibits exit of proteins from the endoplasmic reticulum, selectively inhibited S1 presentation without affecting S3 presentation, suggesting that S1 presentation requires nascent MHC II. The use of agents that perturb endosomal function revealed a requirement for acidification of internalized viral particles for presentation of both epitopes. Notably, all compounds tested had similar effects on presentation of the two epitopes derived from endogenously synthesized HA. Thus, recycling I-Ed molecules appear to be crucial for capturing and presenting an epitope that is revealed in mild acidic conditions following the uptake of virions or the synthesis of Ag, while nascent I-Ed molecules are required for presentation of a second epitope located in a structurally constrained region of the same polypeptide. Viral glycoproteins, such as HA, may have been a major impetus for the evolutionary establishment of this recycling pathway.

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Major histocompatibility complex class II-restricted presentation of an internally synthesized antigen displays cell-type variability and segregates from the exogenous class II and endogenous class I presentation pathways.

Cited by 57 publications

References 62 publications

Functional Macroautophagy Induction by Influenza A Virus without a Contribution to Major Histocompatibility Complex Class II-Restricted Presentation

Functional Macroautophagy Induction by Influenza A Virus without a Contribution to Major Histocompatibility Complex Class II-Restricted Presentation

Presentation of Endogenously Synthesized MHC Class II-Restricted Epitopes by MHC Class II Cancer Vaccines Is Independent of Transporter Associated with Ag Processing and the Proteasome

Presentation by Recycling MHC Class II Molecules of an Influenza Hemagglutinin-Derived Epitope That Is Revealed in the Early Endosome by Acidification

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