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

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

File(s)
2016-OYLER-CYTOKINE_CATCH-AND-RELEASE_COMMUNICATION_ENABLES_LONG-TERM_RESPONSE_TO_TRANSIENT_INFLAMMATION.pdf (9.92 MB)
Permanent Link(s)
https://hdl.handle.net/1813/64686
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Weill Cornell Theses and Dissertations
Author
Oyler, Jennifer
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.

Date Issued
2016
Keywords
Cytokine signaling
•
Dynamics
•
Phosphatidylserine
•
Quantitative biology
•
Systems biology
•
Tumor-Immune interactions
Degree Discipline
Immunology & Microbial Pathogenesis
Degree Level
Doctor of Philosophy
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Rights URI
https://creativecommons.org/licenses/by-nc-nd/4.0/
Type
dissertation or thesis

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