Cytokine Catch-And-Release Communication Enables Long-Term Response To Transient Inflammation

Abstract

In every biological system, individual cells must adapt to ever-changing envi- ronments in order to survive. To adapt, cells translate extra-cellular cues, into phenotypic changes. In the mammalian immune system, cells sample the envi- ronment for pathogens or tumors, and secrete cytokines to alert other cells of the threat. Genome-wide profiling techniques have been instrumental to determine the identity of genes that change in response to cytokines. Often these experiments profile mRNA before and after cytokine stimulation at a single time-point. While single time-point experiments are ideal for identifying which genes changed in re- sponse to a cytokine, studies of gene expression changes over time - dynamics - can reveal novel mechanisms of gene regulation. In vivo, cytokines are often se- creted transiently (hours), yet the dynamics of an acute immune response occur over a week. These widely varied timescales pose a question: how do cells translate short-lived cytokine exposure into long-term gene expression changes that persist for the duration of an immune response? More fundamentally, what mechanisms exist to regulate the duration of a cells? response to a transient stimulus? We studied the transcriptional dynamics of cells exposed to a brief pulse of the cy- tokine Interferon ? and observed long-term up-regulation of genes in the antigen processing and presentation pathway. Transcription of these genes persisted over a timescale of 2 days, before slowly decaying after about one week. By combining mathematical modeling with a variety of experimental techniques, we learned that IFN? is captured by cell surface exposed phosphatidylserine on viable cells. The cytokine is then slowly released to drive persistent transcription of IFN?-response genes in both an autocrine and paracrine manner. Ultimately, this enables a tran- siently produced cytokine to act over a timescale much longer than that of its secretion. This mechanism is a novel mode of cell-to-cell communication, which we coined catch-and-release communication. We observed that catch-and-release communication is a general phenomenon of cell-to-cell communication as it is ap- plicable also to the cytokines Interleukin 12 and 23, and can be executed by diverse cell types from multiple different species. Functionally, catch-and-release signaling could enable cells separated by both space and time to communicate with one another.