CD4 T cells are a crucial component of the adaptive immune system to provide immunological protection to infectious pathogens. Although much is understood about the mechanisms of CD4 differentiation in vitro, how the heterogeneity of CD4 T cell responses is generated and maintained during infection in vivo is unknown, and will be the central focus of this proposal. First, we will establish when the cel fate decisions to diferentiate into distinct CD4 T cell subsets are determined by barcoding and tracing individual naive CD4 T cels. Although we know that CD4 T cell responses are heterogeneous, we do not understand when this choice is made during infection in vivo. Secondly we will address whether inflammatory signals such as IFN-alpha-Beta and IL-6 play reciprocal roles in the differentiation of distinct T{H}1 subsets during LCMV infection. Additionally, we will determine if direct IL-6 signaling plays a role in TH1 memory development during influenza virus infection, and finally we will ask whether Spi2A plays a similar role in protecting memory CD4 T cell from cathepsin-mediated cell death as it does in CD8 T cells. Immunological memory is essential for protection and the experiments proposed will greatly aide in our understanding of how CD4 T cell responses are generated and maintained to memory. Thus, this work wil help to define the mechanisms involved anti-viral CD4 T cell differentiation and memory development in order to develop more eficacious vaccines.

Public Health Relevance

It is important to generate and maintain immunological memory against infections and vaccines to provide protection from reinfection. CD4 T cells are an important component of the adaptive immune system because they play many diverse roles in mediating immunity. This proposal seeks to more fully understand how anti-viral CD4 T cells arise, function, and contribute to the long-lived memory CD4 T cell compartment that protect against secondary infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI094791-01A1
Application #
8312922
Study Section
Special Emphasis Panel (ZRG1-F07-E (20))
Program Officer
Prograis, Lawrence J
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$52,190
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520