The CD8+ T cel response to intracellular pathogens such as bacteria, viruses, and protozoan parasites is a key element of host resistance to 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 how the highly conserved HIF pathway, which plays a central role in regulating metabolism and the response to cellular stress caused by oxygen deficiency/hypoxia, functions in CD8+ T cells. We find that the response to acute and chronic infections are differentially impacted by HIF activity, suggesting that this pathway, which has not been studied in the context of CD8+ T cell responses, controls multiple aspects of the attenuation of effector and memory T cell function, differentiation, and immunopathology. Results from these studies will provide novel insights into the CD8+ 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. Furthermore, we will study the clinical relevance of pharmacologic stabilization of HIF, a molecule targeted in numerous disease contexts, to CD8+ T cell function.
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 cels resulting in proliferation and generation of effector cells, which aces tissues to eliminate infected cels. Effector CD8+ T cels must balance the metabolic requirements of expansion, survival, and cytoxic 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 a profound shift to glycolysis, how changes in metabolic activity influence regulation of effector function, contraction/attenuation of cytolytic activity, and the transition to memory has remained largely unexplored until recently. Several studies have revealed that a metabolic switch from glycolytic to fatty acid metabolism is important for the development of long-lived CD8+ memory cels. These results suggest metabolism influences cell-fate decisions leading to the generation of adaptive immunological memory. Additionally, recent reports suggest the HIF pathway can influence the differentiation of CD4+ T helper subsets and affect autoimmunity-HIF activity apparently favoring Th17 while diminishing iTreg differentiation. Yet, how the function and differentiation of effector and memory CD8+ T cels are linked to metabolic changes influenced by the microenvironment or how HIF regulation of gene expression impacts the CD8+ immune response is unknown. Our preliminary findings show that the von Hippel-Lindau/Hypoxia-inducible Factor (VHL/HIF) pathway, which controls the transcriptionally-induced metabolic responses to hypoxia, profoundly affects the CD8+ T cel response to infection at multiple points including: expansion and expression of effector molecules, upregulation of inhibitory or 'exhaustion' cell-surface receptors, and attenuation of immunopathology. To understand better how the VHL/HIF pathway influences the CD8+ T cels response to infection, we will address the following questions: 1) How does the loss of regulation of the VHL/HIF pathway impact CD8+ T cell immunity? We hypothesize that metabolic shifts regulated by VHL play an important role in T cell survival, responses to infection, and memory formation. Using specific deletion of VHL in mature CD8+ T cells, we will examine T cell homeostasis, responses to primary and secondary infections, and the magnitude, kinetics, and quality of memory formation. 2) How does HIF regulate CD8+ T cell responses? We hypothesize that VHL modulates T cell immunity by attenuating HIF activity. We will study the immune response by T cells with individual and/or compound HIF1?, HIF2? and VHL mutations and will explore how perturbations in HIF activity influence CD8+ T cell metabolism and gene expression. 3) Is there a distinct role for VHL/HIF pathway in CD8+ T cel response to chronic infection? Surprisingly, loss of HIF regulation leads to CD8+ T cel dependent host death in the context of chronic but not acute LCMV infection. We will test the hypothesis that a forced 'effector' metabolic profile may override inhibitory receptor and cytokine inputs and maintain CD8+ T cel effector function in the face of multiple dampening inputs to T cell function. Ultimately our studies will provide a comprehensive understanding of the role for the VHL/HIF pathway in CD8+ T cell immunity, revealing previously unknown functions for HIF and highlighting new strategies to enhance or control the response to intracellular pathogens.
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