Spatial control of immune cell organization and function

Much of the immune system circulates continuously and is therefore distributed in nature. Upon activation, individual immune cells - guided by diffusible chemokines and cytokines - self-organize into localized niches that mediate function. While cytokines are critical for enabling immune cells to organize and clear pathogens, they can also exert harm by damaging healthy tissues during instances of auto-inflammation or exaggerated responses to infection. Regulation of their spatial spread is critical to spare healthy tissues and distant organ systems from their deleterious effects. However, experimental measurements of cytokine spread in different tissues and disease settings have yielded dramatically different results that range from nearest-neighbor interactions to spread over the length of an entire organ. How can we understand and reconcile these vastly distinct measurements? Further, how can such a basic question about immune messengers - how far the message travels - remain unanswered?

Our lab merges biophysical theory, mathematical modeling, and in vitro and in vivo experiments to answer this fundamental question. Specifically, we are developing a general, biophysically-grounded framework that quantitatively predicts cytokine spread based on the properties and cellular organization of different tissues. The simple, tractable, and interpretable nature of our models allows us to anticipate how cytokine spread changes in different tissues, and in healthy immune responses versus inflammatory disease settings. In parallel, we are studying how localized cytokine niches mediate emergent immune functions such as viral containment, immune cell selection and differentiation, and tissue remodeling. To this end, we rely heavily on microscopy and computer-vision guided analysis, enabling us to visualize the spatial organization of cells as they clear pathogens or respond to tumors.

Plain English

The immune system is unlike other organ systems in that it is comprised of cells that are constantly on the move, patrolling the body in search of invaders such as viruses, bacteria, and even cancer cells. When a threat is sensed, immune cells become activated and emit warning signals and cues that recruit other immune cells and tailor the immune response to the threat in question. These signals, which we call chemokines and cytokines, cause immune cells to spatially re-organize into what can be thought of as a temporary mini or micro-organ. In this close-knit environment, the cells interact and specialize to more effectively fight the pathogen. Despite the importance of cytokines to enable the immune system to function properly, they can damage healthy tissues and contribute to many different human diseases. A key factor that controls how potentially dangerous cytokines can be, is the question of how far they can spread away from their source. If they can spread over vast distances - such as to distant organ systems or through an entire tissue, they can potentially harm many cells. However, if they don’t get past a single cell, they might not be able to warn cells that are further away.

Our lab is focused on two major themes relating to cytokine spread. First, we investigate the factors that determine how far cytokines can spread away from their source. We are inspired by the physics that determine how small molecules spread through space and have applied the same math to this biological problem. A major advantage is that our math is generalizable, which gives us flexibility in studying different organs or diseases. Second, we study how cells that assemble into these so-called ‘micro-organs’ change their function and behavior in order to eliminate threats. In addition to using computer models, we use microscopy to directly visualize how cells re-organize in time and space as they destroy viruses and respond to cancer.

Understanding cytokine spread for improved human health

Cytokines are the agents of inflammation, and targeting them to either boost or diminish the immune response is a holy grail for an array of different diseases. However, current therapeutics are not engineered to achieve spatial specificity. Consequently, systemic administration of cytokines (e.g. high-dose Interleukin 2 or pegylated Interferon) suffer from significant side effects, whereas systemic blocking of cytokines (e.g. TNF blockers) increases susceptibility to infection. By studying the factors that control the spatial propagation of cytokines, our work paves the way towards rationally-controlling cytokine localization and creating more targeted interventions for inflammatory illnesses.

About the lab

Jen and Alon are primarily affiliated with the Systems Biology Department and PhD graduate program at Harvard Medical School, and also with the Immunology and Biophysics PhD programs. Jen is originally from central Pennsylvania and went to college in Philadelphia. In 2016, she earned her PhD in Immunology with Grégoire Altan-Bonnet at Weill Cornell in New York City. Alon grew up in Israel, completing his undergrad, Masters, and PhD work in Physics with Oleg Krichevsky at Ben Gurion University. The two met in 2013 at a summer school for Quantitative Biology in New Mexico. They realized that working together was synergistic (and fun!): They could use math and physics to predict how the immune system would behave in different contexts, and then test those predictions using experimental approaches from immunology. Together, Jen and Alon moved to the west coast where they studied the spatiotemporal regulation of cell death during viral infection with Roy Wollman at UCLA. They opened the lab together in 2021.