As for other described cross presentation events depending o

As for other described cross-presentation events depending on type I IFN, we can speculate that in the development of this mechanism, APC are able to generate an immune response against soluble ampa receptor from invading pathogens. This will allow mounting a proper cellular killing arm of defense for non-canonically MHC-I-expressed epitopes. This mechanism itself seems to be evolved from cellular components primarily responsible for different cellular tasks. For example, the Sec61 translocon does not regularly export antigens from endosomes to cytosol for cross-presentation, but rather for the ER-associated degradation machinery (Fossum et al., 2014). The proteasome itself is naturally involved in MHC-I presentation of cytosolic ubiquitinated proteins, whereas the TAP transporter in conjunction with proteasomal processing allow the loading of ER resident MHC-I complexes (Burgdorf et al., 2008). Due to the need of a prompt response after pathogen pattern alert, this machinery can be used near the cell surface to rapidly load epitopes from endocytosed foreign protein on endosome resident MHC-I complexes. This spatial separation could speed the cross-presentation process in a manner that can change the outcome of the battle against an arising infection. Additional studies showed that animals immunized with CDA+OVA were able to mount a potent cellular response against the immunodominant CD8+ restricted SIINFEKL epitope shortly after an immunological recall with OVA nine months after the last immunization. Thus, the use of CDA as adjuvant promotes cellular immunological memory during long periods of time, a critical feature in terms of prophylactic vaccination. To assess the biological significance of the type I IFN-dependent CTL responses stimulated by CDA, vaccinated WT and KO animals were challenged with a recombinant influenza virus carrying a CD8+ immunodominant epitope of OVA. The obtained results demonstrated that an intact type I IFN signaling pathway was crucial for achieving protection against viral challenge. In contrast to WT animals, Ifnar1−/− mice were not protected against infection post vaccination with CDA+OVA. Additional studies suggested that IFN-β is a key mediator for this response, since IFN-β−/− mice were susceptible to viral challenge to a similar extent as Ifnar1−/− and Sting Gt/Gt mice. In conclusion, our studies demonstrated that CTL activation by CDA is strictly dependent on the stimulation of type I IFN-mediated cross-presentation. Type I IFN induction by CDA is also required for optimal stimulation of Th1 responses and induction of multifunctional CD4+ and CD8+ T cells. These findings clarify a key aspect of CDN mode of action, demonstrating that the current assumption that type I IFN induction is dispensable for CDN adjuvanticity should be revised. As demonstrated here, type I IFN is indeed crucial for the most striking capacities of CDN, namely, the stimulation of a CTL response, and the modulation of activity of Th1 cells. This information is crucial for the implementation of CDN-based immune interventions in the clinic, as well as for the generation of CDN derivatives with improved biological properties.
Funding Sources This work was in part supported by grants from the EU (UniVax, contract No. 601738), the grant 0315890 from the BMBF in the context of the program Gerontosys 2 (GerontoShield) and the Helmholtz Association (HAI-IDR). These funding sources had no role in research design, data collection or its analysis, crafting of the manuscript or decision to submit results for publication.
Conflict of Interest Statement
Author Contributions
Introduction As the median age of people living with HIV increases globally (UNAIDS, 2013), there is a growing need to identify and manage the compounded effects of HIV and aging. In geriatrics, restriction enzymes is generally accepted that chronological age may not accurately reflect physiologic reserve. Frailty conceptualizes a “biologic age”, describing an overall physiologic vulnerability to stressors. Frailty is not only a predictor of adverse outcomes during aging, it has also been used to individualize treatment goals for chronic comorbidities to improve health outcomes (Blodgett et al., 2016; Strain et al., 2013). Chronically infected and long-term treated HIV+ people have a heightened risk, and possibly premature onset of, a number of non-AIDS comorbidities including cardiovascular disease, non-AIDS cancers, renal and bone disease, liver disease as well as frailty (Deeks, 2011).