Abstract
Cytotoxic CD8+ T-cells are key players of the immune responses against viruses. During the priming of a CD8+ T-cell response, the activation of a naïve T-cell by a professional antigen presenting cell (APC) involves the induction of various intracellular and metabolic pathways. The modulation of these pathways at the level of APCs or T-cells offers great potential to enhance the induction of robust effector cells and the generation of long-lived memory cells. On the one hand, signaling through pathogen recognition receptors (PRRs) expressed by APCs can greatly influence T-cell priming, and the potential of several PRR ligands as adjuvants are being studied. On the other hand, the engagement of several metabolic processes, at play in APCs and T-cells upon stimulation, implies that modulating cellular metabolism can impact on priming efficacy. Here, we review recent efforts to understand the interplay between PRR mediated signaling and metabolic pathway modulation in this context, through three examples: interplay between TLR4 and fatty acid metabolism, between TLR9 and IDO, and between STING and autophagy. These initial works highlight the potential for harnessing the induction of antiviral CD8+ T-cell responses using synergistic modulation of metabolic and PRR pathways.
Highlights
CD8+ T-cells are major actors of the fight against viruses
pathogen recognition receptors (PRRs) and Metabolism in T-cell Priming by dendritic cells (DCs) [3, 4]
saturated FAs (SFAs)-mediated pro-inflammatory signaling requires their ligation with coenzyme A, a necessary step for SFA oxidation [55], indicating that FAO may be important to facilitate pro-inflammatory effects
Summary
CD8+ T-cells are major actors of the fight against viruses. Owing to their capacity, through T-cell receptor (TCR)—peptide Major Histocompatibility Complex (pMHC) interactions, to recognize a diversity of antigens presented on virus infected cells, CD8+ T-cells can directly kill target cells. SFA-mediated pro-inflammatory signaling requires their ligation with coenzyme A, a necessary step for SFA oxidation [55], indicating that FAO may be important to facilitate pro-inflammatory effects This indicates that the enhancement of FA catabolism may synergize with TLR4 activation to boost T-cell priming. Further studies are necessary to better understand the underlying mechanisms, three hypotheses about the role of FAO in boosting T-cell priming may be proposed: (i) the induction of pro-inflammatory signals; (ii) the provision of additional energy sources to the activated APCs and T-cells, and (iii) the removal of high (and potentially toxic) concentration of SFAs or of FA with inhibitory activity (such as PUFA). The use of IDO inhibitors may reduce immunosuppressive effects of TLR9 ligands and boost its adjuvant activity, favoring the induction of strong antiviral and antitumor T-cell responses (Figure 1B)
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