Controlling Immune Cell Dynamics Using Microfluidics

Immune cells receive time-varying signaling inputs, use gene regulatory pathways to process these signals, and generate outputs by secreting signaling molecules. Characterizing this input-output dynamics helps understanding the underlying regulatory mechanisms and allows manipulating immune interactions for a desired therepeutical outcome. Significant variability in molecular parameters between cells makes time-dependent single-cell and single-molecule analysis crucial in understanding how biological systems operate. I will talk about how we developed automated, high-throughput microfluidic single-cell and single-molecule analysis systems with unprecedented capabilities and measurement accuracy, and how we use them in understanding immune coordination during response to infection. Our recent efforts have resulted in a new set of technologies, including microfluidic systems to measure single-cell cytokine secretion dynamics, cell culture systems that create programmable diffusion-based chemical gradients, devices to measure cell-cell communication via secreted factors, and a new method for digital quantification of proteins and mRNA in the same cell. I will also talk about new biological insight emanated from our experimental and modeling efforts on how single-cells detect and encode dose and frequency information of an input signal using the immune pathway NF-κB, and how molecular noise improves dynamic signal encoding and decoding, and how gene expression and cell fate can be controlled by modulating the temporal profile of biochemical input signals. The primary goal in our combined technology/cell biology effort is to help develop computer models of tissue-level immune response that will serve as a test-bed for drug or genetic perturbations on disease pathways.