This Mentored Quantitative Research Career Development Award (K25) will support the PI in training and research as he makes the transition from physics to immunology. The training and research will be performed at Emory University under the mentorship of Dr. Rustom Antia (theoretical immunology) and co-mentorship of Dr. Rafi Ahmed (experimental immunology). The goal is to establish the PI as an independent researcher at the interface of theoretical and experimental immunology. The training component of the grant includes coursework, seminars and conferences, as well as significant hands-on training in experimental immunology in Dr. Ahmed's lab. The research component of the grant deals with aspects of the CD8 T-cell dynamics in response to antigenic and inflammatory stimuli. The PI will perform detailed quantitative studies to understand how changes in the stimulation lead to changes in growth, death and differentiation of CD8 T-cells. To that end, the PI will develop mathematical models and computational simulations of the CD8 T-cell response. These will be used to analyze data, estimate parameters and test specific hypotheses with regard to the CD8 T-cell dynamics. Additionally, in collaboration with Dr. Ahmed's group, the PI will perform experimental in vitro and in vivo studies of the CD8 T-cell response. The in vivo experiments will use Listeria monocytogenes infection in mice, the in vitro experiments will use direct stimulation factors. In both settings, the stimulation will be varied and CD8 T-cell growth, division and differentiation will be measured. Using the mathematical models and simulation, the data will be analyzed in order to obtain quantitative information about the changes in growth, death and differentiation rates of the CD8 T-cells. The close combination of mathematical models, computational simulations and experiments will result in a detailed and quantitative understanding of the CD8 T-cell dynamics. Such an understanding is of crucial importance for the design and optimization of novel T-cell based vaccines expected to be important to fight pathogens like HIV. Additionally, therapeutic approaches that rely on a CD8 T-cell response, such as combating cancer, will profit from these insights.
|Moulton, Vaishali R; Grammatikos, Alexandros P; Fitzgerald, Lisa M et al. (2013) Splicing factor SF2/ASF rescues IL-2 production in T cells from systemic lupus erythematosus patients by activating IL-2 transcription. Proc Natl Acad Sci U S A 110:1845-50|
|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|
|Moffat, Jessica M; Handel, Andreas; Doherty, Peter C et al. (2010) Influenza epitope-specific CD8+ T cell avidity, but not cytokine polyfunctionality, can be determined by TCR? clonotype. J Immunol 185:6850-6|
|Handel, Andreas; Longini Jr, Ira M; Antia, Rustom (2010) Towards a quantitative understanding of the within-host dynamics of influenza A infections. J R Soc Interface 7:35-47|
|Handel, Andreas; Yates, Andrew; Pilyugin, Sergei S et al. (2009) Sharing the burden: antigen transport and firebreaks in immune responses. J R Soc Interface 6:447-54|
|Handel, Andreas; Antia, Rustom (2008) A simple mathematical model helps to explain the immunodominance of CD8 T cells in influenza A virus infections. J Virol 82:7768-72|
|Handel, Andreas; Yates, Andrew; Pilyugin, Sergei S et al. (2007) Gap junction-mediated antigen transport in immune responses. Trends Immunol 28:463-6|