Inhibitory Pathways Underlying Viral Persistence In Vivo

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ABSTRACT Persistent viral infections involve long-term equilibrium between the pathogen and the immune system. For this, immune cells must adapt in order to keep the pathogen in check while minimizing immunopathology. This immune adaptation is best exemplified by “exhausted” CD8 T cells (TEx), which were first described in a model of murine infection with the persistent lymphocytic choriomeningitis virus (LCMV) isolate Clone 13 (Cl13). In the same model, TEx were also first shown to progressively lose effector functions, express high levels of inhibitory receptors such as program-death-1 (PD-1) and be transcriptionally and epigenetically distinct from other CD8 T cell lineages. TEx were also shown to be a heterogeneous population, with TEx effector-like cells (TEff-like) and stem-like cells (TEx-Stem) emerging as competing differentiation paths within days after infection. TEff- like are short-lived and help to contain early viral spread but can also cause immunopathology. In contrast, TEx- Stem cells self-renew and maintain the TEx pool, being critical for long-term immunity and the success of PD-1- immunotherapy. Thus, understanding the factors that regulate TEx development and maintenance may offer unique insights into how we might exploit these TEx subsets to treat sustained viral infections. White adipose tissue (WAT) and brown adipose tissue (BAT) are both central regulators of whole-body metabolism. WAT stores energy which can be released via lipolysis and provision of free fatty acids (FFA) in times of need. In contrast, BAT is a highly metabolically demanding tissue that consumes great quantities of glucose to maintain core body temperature. Via untargeted metabolomics, we revealed a striking nutritional shift within the first ten days after LCMV Cl13 infection. In brief, we detected a profound systemic increase in FFA and a reduction in glucose, which coincided with WAT lipolysis and changes in BAT thermogenesis. Remarkably, mice with genetic inhibition of WAT lipolysis exhibited reduced FFA, decreased TEx-Stem and enhanced expression of the effector molecule granzyme B (GrzB). On the other hand, absence of BAT thermogenesis led to enhanced GrzB and CD8-T-cell-mediated death, while stimulation of BAT thermogenesis reduced effector CD8 T cells and delayed viral control. These results provide the first evidence that virus- specific CD8 T cells can be regulated by distant, non-immune, metabolically relevant tissues after an infection. Our overall goal is to leverage these exciting preliminary data and investigate the unique hypothesis that WAT (Aim 1) & BAT (Aim 2) regulate CD8 T cell responses during persistent infection through the provision and restriction of available nutrients (FFA and glucose, respectively), which in turn influence CD8-T-cell metabolism and differentiation, ultimately affecting the infection outcome. This work will establish the first foundational principles for a long-distance regulation of antiviral CD8 T cells by metabolically-relevant non-immune tissues, opening both a paradigm-shifting perspective to consider the host's bioenergetics when studying antiviral immunity and the possibility of targeting a patient's global metabolism to alleviate infectious diseases.