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Type I IFN ineffectively activates neonatal dendritic cells limiting respiratory antiviral T-cell responses
Annie W Lau-Kilby1, Mathilde Turfkruyer1, Margaret Kehl1
1Laboratory of Infectious Diseases and Host Defense, Department of Pediatrics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Insights
Neonatal dendritic cells (DCs) fail to respond to type I interferons (IFN-I), impairing T-cell activation against viral respiratory infections. This discovery offers a new target for infant vaccine development against viruses like RSV.
Area of Science:
- Immunology
- Virology
- Neonatal immunology
Background:
- Infant T-cell responses are insufficient against viral respiratory diseases.
- Neonatal dendritic cells (DCs) exhibit defective T-cell activation, hindering vaccine design.
- Understanding neonatal DC function is crucial for immunomodulation strategies.
Purpose of the Study:
- To characterize neonatal DC sub-specialization and function in response to viral antigens.
- To investigate the mechanisms behind defective T-cell activation in neonatal DCs.
- To identify potential targets for improving infant vaccine efficacy.
Main Methods:
- Engineered respiratory syncytial virus (RSV) to express ovalbumin for tracking antigen-presenting DCs.
- Utilized murine models to study neonatal conventional DC1s (cDC1s) in vivo.
- Assessed the response of neonatal cDC1s to type I interferons (IFN-I) during viral antigen presentation.
Main Results:
- Murine neonatal cDC1s efficiently presented RSV-derived antigen, challenging global immaturity paradigms.
- Neonatal cDC1s failed to upregulate costimulatory molecules in response to IFN-I during viral antigen presentation.
- Human neonatal cDC1s also exhibited deficient IFN-I responses, independent of infection.
Conclusions:
- Neonatal cDC1s display a distinct, deficient response to IFN-I, increasing infant susceptibility to viral infections.
- This impaired IFN-I signaling pathway is a critical factor in poor neonatal antiviral T-cell immunity.
- The findings provide a novel target for developing effective infant vaccines, particularly for RSV.
Abstract:
Insufficient T-cell responses contribute to the increased burden of viral respiratory disease in infancy. Neonatal dendritic cells (DCs) often provide defective activation of pathogen-specific T cells through mechanisms that are incompletely understood, which hinders vaccine design for this vulnerable age group. Enhancing our characterization of neonatal DC sub-specialization and function is therefore critical to developing their potential for immunomodulation of T-cell responses. In this study, we engineered respiratory syncytial virus (RSV) to express a model protein, ovalbumin, to track antigen-presenting DCs in vivo. We found that murine neonatal conventional DC1s (cDC1s) efficiently migrated and presented RSV-derived antigen, challenging the paradigm that neonatal DCs are globally immature. In a key observation, however, we discovered that during infection neonatal cDC1s presenting viral antigen were unable to upregulate costimulatory molecules in response to type I interferons (IFN-I), contributing to poor antiviral T-cell responses. Importantly, we showed that the deficient response to IFN-I was also exhibited by human neonatal cDC1s, independent of infection. These findings reveal a functionally distinct response to IFN-I by neonatal cDC1s that may leave young infants susceptible to viral infections, and provide a new target for exploration, in light of failed efforts to design neonatal RSV vaccines.
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