Appay, V. | Search bioRxiv

bioRxiv2025

Human type-I interferon omega holds potent antiviral properties and promotes cytolytic CD8+ T cell responses

The type-I interferon family is well known for its critical role in innate immunity. It comprises several members, among which IFN-2 and IFN-{beta} are the most extensively studied, with important antiviral and immune-modulatory functions. Recent findings linking autoantibodies against type-I interferons to severe COVID-19 suggest a potential role for IFN-{omega} in combating SARS-CoV-2 infection. However, little is known about human IFN-{omega}, as most research on this interferon has been conducted in feline models. Here, we demonstrate that human IFN-{omega} is secreted at levels comparable to those of IFN-2 or IFN-{beta} upon stimulation with inflammatory agonists and triggers a robust antiviral response, inhibiting SARS-CoV-2 infection in vitro. Moreover, IFN-{omega} enhances the effector functions of antigen-specific CD8+ T cells primed de novo from healthy donor cells, highlighting its capacity to promote strong cellular immunity. Our results position IFN-{omega} as a key member of the type-I interferon family, with promising potential for therapeutic and vaccine applications. Author SummaryType-I interferons are pleiotropic cytokines, including IFN- and IFN-{beta}, which are well known for their antiviral activities. Here, we report on the functional characteristics of human IFN-{omega}, a neglected member of the type-I IFN family, which has primarily been studied in feline models. We show here that human IFN-{omega} induces intense downstream signaling in cells resulting in the upregulation of antiviral genes, and efficient restriction of SARS-CoV-2 replication. IFN-{omega} also promotes the acquisition of strong cytolytic functions by antigen primed CD8+ T cells. Overall, our findings portray human IFN-{omega} as a major antiviral molecule, similar to the well-studied and highly effective IFN-2. The secretion of IFN-{omega} upon infection is likely to be crucial for effective control of multiple viruses, advocating for its use in therapeutic approaches in humans.

immunology↗

bioRxiv2020

Altered basal lipid metabolism underlies the functional impairment of naive CD8+ T cells in elderly humans

BackgroundAging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered antigens. The mechanisms that underlie this phenomenon have nonetheless remained unclear. MethodsBiochemical and functional properties of naive CD8+ T cells were characterized and compared between middle aged and older individuals. FindingsWe identified an age-related link between altered basal lipid metabolism in naive CD8+ T cells and their impaired responsiveness to stimulation, characterized by low proliferative potential and susceptibility to apoptosis. Reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, improved the functional capabilities of naive CD8+ T cells in elderly subjects. InterpretationInterventions that favor lipid catabolism may find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against emerging pathogens or tumors. FundingA full list of the funding sources is detailed in the Acknowledgment section of the manuscript. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSOld subjects are highly susceptible to infections and tumors and usually present with low responses to vaccine. This is mainly due to the age-related loss of primary immune resources, i.e. a quantitative decline of naive CD8+ T cells. Nonetheless, few studies have also underlined, within this cell subset, qualitative defects in elderly subjects. Added value of this studyConsidering the well-demonstrated link between nutrient usage and lymphocyte functions, we characterized the bioenergetics features of old naive CD8+ T cells. Our data show an age-dependent altered basal metabolism in this cell subset, mostly at the levels of fatty acids and mitochondrial functions. These alterations were associated with functional defects which were partially reverted through the use of lipid-lowering strategies. Implications of all the available evidenceThis study highlights the potential role of an altered cellular lipid metabolism in immunosenescence, providing clues to understand the epidemiological profile of emerging infections or tumors and to develop preventive and therapeutic strategies based on metabolic manipulation.

immunology↗