Abstract/Details

Elucidation of MHC class II-restricted antigen processing pathways using influenza virus epitopes


2010 2010

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Abstract (summary)

The processing and presentation of antigen is the backbone of an optimal T cell response. This field is generally divided into MHC class I molecules, which are responsible for the presentation of antigenic peptides to CD8+ T cells, and MHC class II molecules that do the same for CD4+ T cells. While much is understood about the pathways comprising this field, there are mechanisms still left uncovered. Herein, we focus on the processing of proteins for loading onto MHCII molecules using influenza A virus as a model system. We concentrate on three epitopes, all restricted to the same murine MHCII molecule, I-Ed. The first is derived from hemagglutinin (HA aa107-119, S1), and is generated in a conventional manner as it requires the harsh environment of the late endosome. The second originates in neuraminidase (NA aa79-93, NA79), and is alternatively processed with proteasome- and TAP- dependence. The last is also from hemagglutinin (HA aa302-313, S3), and can be presented like NA79, or from an exogenous source on recycling MHCII molecules. Using these epitopes, we demonstrate that HA can be transferred on exosomes and act as a source of antigen for S1 presentation in uninfected cells. Most noteworthy was the enhancement of presentation by the receptor-attachment ability of HA on the surface of exosomes. Next, we explore the differential proteolytic requirements of S1 compared to NA79, and illustrate a destructive function for asparaginyl endopeptidase in the processing of NA79. Additional studies aim at dissecting the role of reductases in the degradation of S1. Also, an observed skewing of the influenza CD4+ T cell response towards the disulfide-linked glycoproteins (HA and NA) is discussed. Further, we explain a system developed to identify the subcellular compartments where the aforementioned epitopes are loaded onto MHCII molecules. Finally, a model is suggested whereby exosomes are a more advantageous antigen source compared to free virus particles, and the implications of this research for the advancement of vaccine design and immunotherapeutic treatments are discussed.

Indexing (details)


Subject
Virology;
Immunology
Classification
0720: Virology
0982: Immunology
Identifier / keyword
Health and environmental sciences, Biological sciences, Antigen, Exosome, Influenza virus epitopes, Mhcii, Presentation, Processing pathways
Title
Elucidation of MHC class II-restricted antigen processing pathways using influenza virus epitopes
Author
Testa, James S., Jr.
Number of pages
173
Publication year
2010
Degree date
2010
School code
0272
Source
DAI-B 72/05, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124518954
Advisor
Eisenlohr, Laurence C.
Committee member
Alugupalli, Kishore; Marks, Michael; Taraschi, Theodore; Zhang, Jianke
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
3444354
ProQuest document ID
858501785
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/858501785
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