2025/07/01 by Xiaolu Guo, Adewunmi Adelaja, Apeksha Singh +2 · 1 voice
Immunology and Microbiology · #Immune Response and Inflammation #T-cell and B-cell Immunology #Immunotherapy and Immune Responses
paper · pdf · doi:10.1038/s41467-025-60901-3
openalex publication_date 2025/07/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31
Macrophages initiate pathogen-appropriate immune responses with the activation dynamics of transcription factor NFκB mediating specificity. Live-cell imaging revealed the stimulus-response specificity of NFκB dynamics among populations of heterogeneous cells. To study stimulus-response specificity beyond what is experimentally accessible, we develop mathematical model simulations that capture the heterogeneity of stimulus-responsive NFκB dynamics and the stimulus-response specificity performance of the population. Complementing experimental data, extended-dose response simulations improved channel capacity estimates. By collapsing parameter distributions, we locate information loss to receptor modules, while the negative-feedback-containing core module shows remarkable signaling fidelity. Further, constructing virtual single-cell networks reveals the stimulus-response specificity of single cells. We find that despite stimulus-response specificity limitations at the population level, the majority of single cells are capable of responding specifically to immune threats, and that the few instances of stimulus-pair confusion are highly uncorrelated. The diversity of blindspots enable small consortia of macrophages to achieve perfect stimulus distinction.