I am seeking a career transition award to assist my studies of immunodominance hierarchies in the influenza infection model. I have a strong background in host-pathogen interactions in parasitic and viral models from my graduate and postdoctoral work, respectively. While a significant part of my postdoctoral work has focused on CD4+ T cell activation and expansion in influenza, I have also developed several infection models for the investigation of immunodominance. 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 models. It is still uncertain why one response dominates over other responses, however it is clear that more than one parameter is responsible. In the influenza infection model in BL/6 mice we observe a striking immunodominance hierarchy. 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. In this proposal, I seek to test a mathematical model of immunodominance I have generated as the central hypothesis. To test this hypothesis, I propose the development of more quantitatively precise techniques for measuring both epitope density and precursor frequency. 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. The mathematical models in this proposal 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI077714-02
Application #
7937978
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2009-09-24
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$108,000
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Dash, Pradyot; Wang, George C; Thomas, Paul G (2015) Single-Cell Analysis of T-Cell Receptor ?? Repertoire. Methods Mol Biol 1343:181-97
Russ, Brendan E; Olshanksy, Moshe; Smallwood, Heather S et al. (2014) Distinct epigenetic signatures delineate transcriptional programs during virus-specific CD8(+) T cell differentiation. Immunity 41:853-65
Thomas, Paul G; Handel, Andreas; Doherty, Peter C et al. (2013) Ecological analysis of antigen-specific CTL repertoires defines the relationship between naive and immune T-cell populations. Proc Natl Acad Sci U S A 110:1839-44
La Gruta, Nicole L; Thomas, Paul G (2013) Interrogating the relationship between naïve and immune antiviral T cell repertoires. Curr Opin Virol 3:447-51
Zloza, Andrew; Kohlhapp, Frederick J; Lyons, Gretchen E et al. (2012) NKG2D signaling on CD8ýýý T cells represses T-bet and rescues CD4-unhelped CD8ýýý T cell memory recall but not effector responses. Nat Med 18:422-8
Wang, George C; Dash, Pradyot; McCullers, Jonathan A et al. (2012) T cell receptor ?? diversity inversely correlates with pathogen-specific antibody levels in human cytomegalovirus infection. Sci Transl Med 4:128ra42
Billam, Padma; Bonaparte, Kathryn L; Liu, Jie et al. (2011) T Cell receptor clonotype influences epitope hierarchy in the CD8+ T cell response to respiratory syncytial virus infection. J Biol Chem 286:4829-41
Dash, Pradyot; McClaren, Jennifer L; Oguin 3rd, Thomas H et al. (2011) Paired analysis of TCR? and TCR? chains at the single-cell level in mice. J Clin Invest 121:288-95
Moon, James J; Dash, Pradyot; Oguin 3rd, Thomas H et al. (2011) Quantitative impact of thymic selection on Foxp3+ and Foxp3- subsets of self-peptide/MHC class II-specific CD4+ T cells. Proc Natl Acad Sci U S A 108:14602-7
Rawlings, Jason S; Gatzka, Martina; Thomas, Paul G et al. (2011) Chromatin condensation via the condensin II complex is required for peripheral T-cell quiescence. EMBO J 30:263-76

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