Multimeric peptide-MHC Class I (pMHCI) reagents enable the detection, characterization and purification of epitope-specific CD8+ T cells by flow cytometry and have greatly facilitated studies to advance our understanding of virus-specific CD8+ T cells. Studies that examine the development and evolution of virus- specific and cross-reactive CD8+ T cells are an important focus of this Program Project. Project I (Luzuriaga) will use the Epstein Barr virus (EBV) model of persistent viral infection to characterize the lineage relationship between effector and memory responses and the factors that influence the evolution of antigen-specific CD8+ T cell responses into the memory CD8+ T cell repertoire. Project 2 (Selin) will determine how cross-reactivity impacts CD8+ T cell selection and function, and influences disease outcome. The Tetramer Core will produce the large quantities of high-quality reagents crucial for both of these projects in a timely and cost effective manner. We utilize well-established techniques for the expression and purification of MHC I molecules, refolding with peptide epitopes, and conjugation with fluorochromes. We plan to expand our inventory to include additional pMHCI reagents that will enable a broader analysis of EBV-specific CD8+ T cell responses and will utilize newer fluorescent labels, such as QDots, to facilitate the simultaneous analyses of multiple EBV epitope-specific CD8+ T cell responses by multiparameter flow cytometry. Over the past funding period, we have developed reagents with altered CD8 binding capacity to better define differences in avidity of T cell receptor interactions with cognate antigen. We will also develop bi-specific heterodimers for characterizing cross-reactive CD8+ T cells.
A key goal of this Program Project is to use the EBV model of persistent infection to characterize the development and evolution of virus-specific and cross-reactive CD8+ T cells. These studies will improve our understanding of the development of CD8+ T cell responses to viral infections, and will allow us to better understand how EBV-specific and cross-reactive CD8+ T cells contribute to either control of viral replication or immune pathology. The Tetramer Core will produce pMHCI reagents crucial for these studies.
|Aslan, Nuray; Watkin, Levi B; Gil, Anna et al. (2017) Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires. MBio 8:|
|Song, InYoung; Gil, Anna; Mishra, Rabinarayan et al. (2017) Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope. Nat Struct Mol Biol 24:395-406|
|Watkin, Levi B; Mishra, Rabinarayan; Gil, Anna et al. (2017) Unique influenza A cross-reactive memory CD8 T-cell receptor repertoire has a potential to protect against EBV seroconversion. J Allergy Clin Immunol 140:1206-1210|
|Gil, Anna; Yassai, Maryam B; Naumov, Yuri N et al. (2015) Narrowing of human influenza A virus-specific T cell receptor ? and ? repertoires with increasing age. J Virol 89:4102-16|
|Gil, Anna; Kenney, Laurie L; Mishra, Rabinarayan et al. (2015) Vaccination and heterologous immunity: educating the immune system. Trans R Soc Trop Med Hyg 109:62-9|
|Greenough, Thomas C; Straubhaar, Juerg R; Kamga, Larisa et al. (2015) A Gene Expression Signature That Correlates with CD8+ T Cell Expansion in Acute EBV Infection. J Immunol 195:4185-97|
|Renzette, Nicholas; Somasundaran, Mohan; Brewster, Frank et al. (2014) Epstein-Barr virus latent membrane protein 1 genetic variability in peripheral blood B cells and oropharyngeal fluids. J Virol 88:3744-55|
|Chen, Alex T; Cornberg, Markus; Gras, Stephanie et al. (2012) Loss of anti-viral immunity by infection with a virus encoding a cross-reactive pathogenic epitope. PLoS Pathog 8:e1002633|
|Tracy, Sean I; Kakalacheva, Kristina; Lunemann, Jan D et al. (2012) Persistence of Epstein-Barr virus in self-reactive memory B cells. J Virol 86:12330-40|
|O'Bryan, Joel M; Potts, James A; Bonkovsky, Herbert L et al. (2011) Extended interferon-alpha therapy accelerates telomere length loss in human peripheral blood T lymphocytes. PLoS One 6:e20922|
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