The CD8+ T cell response is a key element of host resistance to viral infections. To generate a robust and effective immune response, CD8+ T cells must integrate pathogen-derived and micro-environmental signals, including availability of nutrients and oxygen. Together these signals regulate the changes necessary for the dramatic expansion of effector T cells armed to eliminate pathogens and for the generation of immunological memory. In these studies, we will work to understand the transcriptional control of CD8+ immunity using novel strategies that use function-based screening approaches to identify molecules that control formation of protective immunity. In particular, we will explore how T cell function and memory formation is impacted at the transcriptional level within the context of dermal infection. Results from these studies will provide novel insights into T cell immunity, a topic of significance in the development of treatment strategies and vaccines for chronic infections, emerging infectious agents, and microorganisms relevant to biodefense.
The CD8+ T cell immune response is essential for the clearance of many intracellular pathogens including viruses, bacteria and protozoan parasites. Infection initiates a program of differentiation by CD8+ T cells resulting in proliferation and generation of effector cells, which access tissues to eliminate infected cells. Effector CD8+ T cells must balance the metabolic requirements of expansion, survival, and cytotoxic function with the limiting nutrient and oxygen availability of infected tissues. Furthermore during the resolution of infection, a population of long-lived memory cells emerges to provide protection from pathogen re-exposure. While T cell activation induces profound changes in gene expression, relatively little is known about how the Micro-environmental milieu impacts the transcriptional network controlling T cell effector function and memory differentiation. In this project we will define the transcriptional regulators of CD8+ effector and memory cells and examine the impact of microenvironment on gene expression in the context of dermal infection. The specific objectives of this project are to: 1) Define transcriptional regulators promoting the formation of Id3 CD8+ memory precursors and the role for IdS in established memory cell populations. 2) Establish the complete transcriptional network influencing effector and memory cell differentiation in CD8+ T cell responses using novel in vivo function-based genetic screening. 3) Identify transcription factors influencing effector and memory cell differentiation in CD4+ T cell responses. 4) Explore the transcriptional control of antiviral T cell responses specific to the dermal microenvironment to understand how hypoxia and altered metabolic demands encountered in infected tissues impact function differentiation of T cells. Together these studies will inform therapeutic strategies to combat viral infection.
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|Nance, J Philip; BÃ©langer, Simon; Johnston, Robert J et al. (2015) Cutting edge: T follicular helper cell differentiation is defective in the absence of Bcl6 BTB repressor domain function. J Immunol 194:5599-603|
|Crotty, Shane; Pipkin, Matthew E (2015) In vivo RNAi screens: concepts and applications. Trends Immunol 36:315-22|
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