Microheterogeneity in the Kinetics and Sex-Specific Response to Type I IFN

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Type I interferons (IFNs) rapidly induce IFN signature genes (ISGs).
• Cell population studies suggest coordinated ISG expression, but individual cell responses remain unclear.
• Understanding ISG heterogeneity is crucial for deciphering immune responses.

Purpose of the Study:

• To investigate the heterogeneity of ISG induction kinetics at the single-cell level.
• To compare ISG response dynamics across different immune cell types (macrophages, B cells, T cells).
• To identify potential sex-based differences in IFN responses.

Main Methods:

• Time-resolved single-cell RNA sequencing of mouse immune cells post-IFN stimulation.
• Analysis of ISG induction kinetics and gene module coordination.
• Velocity analysis to assess response progression and transcription rates.

Main Results:

• ISGs were generally induced in concert across all cell types.
• Macrophages exhibited homogeneous ISG kinetics, while B and T lymphocytes showed greater diversity, including nonresponsive cells.
• Female cells displayed faster ISG induction kinetics than male cells.
• Negative feedback rapidly curtailed responses in B and T lymphocytes compared to macrophages.

Conclusions:

• While ISGs act as a cohesive gene block, their response kinetics exhibit significant cell-type and sex-specific variations.
• These kinetic differences, particularly sex differences, may influence differential susceptibility and outcomes in viral infections.
• Single-cell analysis reveals crucial heterogeneity masked by population-level studies.