Activation of naive CD4+ T cells (TCD4+) is driven by MHC class II (MHCII)-bound peptides (epitopes) displayed at the surfaces of dendritic cells (DCs) that have trafficked from sites of infection to regional lymph nodes. While most studies concentrate on the primary response, the majority of pathogen exposures in nature are repeat encounters that play out in decidedly different contexts. Indeed, we hypothesize that activation of memory TCD4+, increasingly appreciated as a key aspect of the recall response, is fundamentally distinct. This is attributable in large part to the presence of antigen-specific B cells, which possess unique antigen processing capabilities. Consequently, this drives a significant shift in the TCD4+ specificities that emerge from recall vs. primary responses. Through well-established influenza models that play to the experience of both co-PIs, this hypothesis will be pursued via two tightly linked specific aims. In the first aim the impact of B cells in the secondary response will be assessed by: a) selectively eliminating or turning on MHCII on memory B cells prior to a secondary challenge, and b) restricting flu protein expression to specific cell types by engineering viruses that contain selective miRNA targeting sequences. In the second aim the antigen processing and presenting capabilities of ex vivo flu-specific B cells vs. DCs will be assessed by in vitro TCD4+ activation assays. The prediction is that the observed differences between these antigen presenting cell (APC) types will provide a basis for the TCD4+ specificities that are amplified during the secondary vs. primary responses. This project is expected to set the stage for studies that explore the processing machinery that facilitates B cell-mediated presentation, the role of memory B cells in responses to other pathogens, as well as more applied studies that leverage resulting principles to enhance rational vaccine design.

Public Health Relevance

Humans are repeatedly infected with pathogens over their lifetimes; however, most of what we know about immune responses derives from laboratory studies of animals recovering from primary infections. In this proposal, we will elucidate mechanisms that promote activation of helper T cells, key participants in the host response, in animals with previous exposure to influenza virus. Outcomes of this research could significantly enhance the process of rational vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI110848-01A1
Application #
8823195
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2014-12-01
Project End
2015-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Forsyth, Katherine S; Eisenlohr, Laurence C (2016) Giving CD4+ T cells the slip: viral interference with MHC class II-restricted antigen processing and presentation. Curr Opin Immunol 40:123-9