Abstract/Details

MHC class II restricted processing of endogenous antigens during viral infection


2011 2011

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Abstract (summary)

MHC class II presented peptides are derived from both exogenous (extracellular) and endogenous (biosynthesized) sources of antigen. Several endogenous antigen processing pathways have been reported, with recent studies focusing on a macroautophagy dependent pathway of endogenous processing. In this pathway, autophagosomes capture viral antigens and traffic them to the late endosome compartment for processing and subsequent loading onto MHC class II molecules. Although macroautophagy presentation of several individual epitopes has been reported, little is known about the relative contribution to global CD4 + T cell responses against complex antigens. Here, we demonstrate that influenza virus 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 antigens. However, validated 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.

It is also apparent that the endogenous processing pathways are highly regulated which could impact both autophagy mediated and proteasome mediated presentation. Although the role of cytokines and TLR agonists in antigen presentation is well studied, much less is known about the role the virus itself has on this process. Here, we demonstrate markedly different presentation levels of the endogenous epitopes S3 and NA79 but nearly identical presentation levels of the classical exogenous S1 epitope between two variants of the PR8 strain of influenza virus. This inhibition was not due to inhibition of protein synthesis but rather to the presence of defective interfering particles in one of the viral preparations. We termed the variant the led to robust endogenous presentation wild-type and the variant containing defective interfering particles DI PR8. This inhibition in presentation could be reproduced by overexpressing RIG-I, a cytosolic pattern recognition receptor, implicating DI particle (RNA intermediates) association with RIG-I in the alteration of endogenous processing.

Indexing (details)


Subject
Cellular biology;
Immunology
Classification
0379: Cellular biology
0982: Immunology
Identifier / keyword
Health and environmental sciences; Biological sciences; Antigen processing; Influenza A virus; MHC class II; Macroautophagy; Proteasomes
Title
MHC class II restricted processing of endogenous antigens during viral infection
Author
Comber, Joseph D.
Number of pages
110
Publication year
2011
Degree date
2011
School code
0272
Source
DAI-B 72/08, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124655819
Advisor
Eisenlohr, Laurence C.
Committee member
Calkins, Catherine; Paumet, Fabienne; Sykulev, Yuri
University/institution
Thomas Jefferson University
Department
Immunology and Microbial Pathogenesis
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3456238
ProQuest document ID
871452543
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/871452543
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