Immunodominance hierarchies in influenza specific CD8+ T cell responses
EMSL Project ID
34745
Abstract
The phenomenon of immunodominance has been observed in B cell, CD4+ T cell and CD8+ T cell antigen-specific responses in virtually all types of infection and in tumor immunity model. It is still uncertain why one response dominates over other responses, however it is clear that more than one parameter is responsible. There is no linear correlation between one factor and immunodominance hierarchies that is consistently predictive. In the influenza infection model in BL/6 mice we observe a striking immunodominance hierarchy, particularly in the secondary response, where the NP epitope dominates by a factor of 8-to-10 fold over the other responses; in the primary response the NP response is co-equal, or often lower in number, than many other responses. Understanding immunodominance is crucial to rational vaccine design and to immunotherapy for persistent infections such as HIV, or for anti-tumor immune treatments. Currently, estimating a "good" epitope in vivo relies on empirical observation and experimentation; we have few tools for predicting epitopes that generate a response that is robust, will successfully avoid immune escape, or be protective. As viral vectors are becoming more common components of experimental vaccination regimens to stimulate strong CD8+ T cell immunity, it is important to understand how the host response to epitopes within the viral vector might alter responses to the desired immune targets.
Our study arises out of a series of observations suggesting precursor frequency and epitope density are the primary determinants of CD8+ T cell immunodominance hierarchies in the influenza model. However, our inability to accurately measure these two parameters has limited our attempts to directly model how they might influence immunodominance in in vivo models. Current techniques available for estimating these quantities are crude at best and their accuracy remains an open question. In this proposal, we seek to continue developing more quantitatively precise techniques for measuring both epitope density and precursor frequency and to extend these studies towards developing a fundamental model of the formation of immunodominance hierarchies. The model we propose here is the central hypothesis of the proposal. The proposal is focused on developing and implementing the techniques to measure the variables necessary for a thorough assessment of the model and the refinement of the model following the collection of these data. These models and parameter measurements should allow a more prospective approach towards therapeutic design as well increasing our understanding of the essential structure of CD8 T cell responses.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2009-10-01
End Date
2012-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
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Smallwood HS, D Lopez-Ferrer, and TC Squier. 2011. "Aging Enhances the Production of Reactive Oxygen Species and Bactericidal Activity in Peritoneal Macrophages by Upregulating Classical Activation Pathways." Biochemistry 50(45):9911-9922. doi:10.1021/bi2011866
Smallwood H S,Duan S ,Morfouace M ,Rezinciuc S ,Shulkin B L,Shelat A ,Zink E M,Milasta S ,Bajracharya R ,Oluwaseum A J,Roussel M F,Green D R,Pasa Tolic L ,Thomas P G 2017. "Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention" Cell Reports 19(8):1640-1653. 10.1016/j.celrep.2017.04.039