Transiently heritable fates and quorum sensing drive early IFN-I response dynamics

Abstract

Type I Interferon (IFN-I)-mediated antiviral responses are central to host defense against viral infections. Crucial is the tight and well-orchestrated control of cellular decision-making leading to the production of IFN-Is. Innovative single-cell approaches revealed that the initiation of IFN-I production is only limited to a fraction of 1-3% of the total population, both found in vitro and in vivo, which were thought to be stochastically regulated. To challenge this dogma, we addressed the influence of various host-intrinsic factors, both stochastic and epigenetic, on dictating early IFN-I responses. Hypomethylating drugs increased the percentage of responding cells. Next, with the classical Luria-Delbrück fluctuation test, we provided evidence that the fate of becoming a responding cell is transiently heritable. Finally, while studying varying cell-densities, we substantiated an important role for quorum sensing, which was verified by mathematical modeling. Together, this systems immunology approach opens up new avenues to progress the fundamental understanding of cellular decision-making during early IFN-I responses, which can be translated to other (immune) signaling systems, and ultimately will improve IFN-I based immune therapies.

Probing transient memory of cellular states using single-cell lineages

“…Inclusion of density-dependent effects where transition rates themselves depend on the local cell density. For example, the rates k 1 and k 2 can depend on the fraction of cells in State 2 capturing some form of quorum sensing, which is well-known in microbial populations and also reported in immune cells (Antonioli et al, 2018;Van Eyndhoven et al, 2022). 3.…”

“…Similar digital responses in subpopulations were also seen in primary organoids with individual cells showing switch-like epigenetic modifications of the TLR2 locus (Clark et al, 2021 ). Cell density can alter the fraction of responding cells, and the fluctuation test was recently used to show that this phenomenon arises from a higher switching rate into responder cell states at lower densities, indicating a form of immune quorum sensing (Antonioli et al, 2018 ; Van Eyndhoven et al, 2021 , 2022 ).…”