At a glance
A new set of tools allows researchers to tag cells that receive signals from immune molecules called cytokines.
The method reveals, for the first time, when, where, and how cells react and allows researchers to follow the responding cells over time.
The work offers insight into a largely unknown aspect of the body’s immune responses and could point to new treatments for a variety of diseases.
The future of federally funded research at Harvard Medical School — supported by taxpayers and done in service to humanity — remains uncertain. Learn more.
Scientists in the Blavatnik Institute at Harvard Medical School and MIT have created a new family of tools that, for the first time, illuminates the missing half of how the immune system uses molecules called cytokines to communicate with the rest of the body.
The work, described Jan. 7 in Cell and supported with funding from the U.S. federal government, could provide a transformative view of immune response and disease, which in turn could lead to new drugs for infectious diseases, cancer, allergies, and autoimmune diseases.
Immune cells use cytokines to communicate with other cell types. These messages play many important roles in protecting the body and maintaining a stable, steady internal environment, including initiating, coordinating, and terminating immune responses such as fever and inflammation.
Scientists know a lot about how, when, and why immune cells create and send out cytokines and have used this information to create important medicines to fight infectious diseases, cancers, and autoimmune diseases. However, scientists have had a hard time identifying which cells receive specific cytokine signals as well as when and how they respond when called upon.
“Imagine you’re watching a baseball game, and all you can see is the hitters,” said study co-senior and lead author Jun Huh, associate professor of immunology at HMS. “It’s very difficult to understand what’s happening if you don’t know anything about who the players are in the field, where they are, or what they do if they catch the ball.”
The new tools, called cytokine cellular locating platforms (CyCLoPs), at last allow researchers to tag the cells that respond to specific cytokines in particular situations.
“We have a tool that gives us a better view of the whole game,” Huh said. “This way we can follow all of the players on the field over an extended time.”
New tool to visualize cytokine receptor activity
Huh became interested in solving the problem of tracking cytokine responses because it stood in the way of his desire to understand how the immune system moderates its responses, especially in the context of immune disease and neurological disorders, and to capitalize on that knowledge to make better drugs.
CyCLoPs works like a biological highlighter: When a cytokine binds to its receptor on a cell, the tool tags the cell with a fluorescent marker.
For this study, tests in cell cultures showed that CyCLoPs produced a strong, clear signal and could be adapted to detect many different cytokines.
The researchers also developed two preclinical mouse models that allowed them to test CyCLoPs in organs and tumors. With one mouse type, they tagged cells that responded to the cytokine interleukin-17A (IL-17A) in the lining of the lower small intestine after exposure to a particular gut bacterial species. With the other mouse type, they found that the cytokine interferon gamma (IFN-γ), which is thought to protect against tumors, in this case actually weakened a group of immune “killer” T cells, when tagged cells showed signs of being less effective at killing the cancer cells.
Because the fluorescent markers that CyCLoPs delivers make their way to cell nuclei, each tagged cell — and its descendants — can be found and studied later.
This means the durable, genetically traceable tags will make it possible to, for example, see how cells that have responded to cytokines react if they are later re-exposed to the same immune stimuli that triggered the original cytokine release.
Next steps
The new technology still has limitations. The strength of the cytokine reception signal varies in different cell types, which means it’s not an effective tool for comparing the relative strength of response in different cell types, Huh said.
CyCLoPs had a particularly hard time labelling cell types that don’t proliferate, including neurons, which is ironic, since the researchers originally set out to build the tool to explore how cytokines help the immune system interact with the nervous system.
Huh hypothesizes that this may be due either to the large size and elongated shape of neurons, or to the architecture of the nucleus of nondividing cells being less compatible with the tagging system.
“We’re very excited about what this new system can do, but we’re also going to keep expanding its capabilities,” he said. “We’re already working on CyCLoPs 2.0.”
Authorship, funding, disclosures
Gloria Choi of MIT is co-senior author. Additional authors include Guangqing Lu, Shanshan Zhang, Mengyang Feng, Eunha Kim, Daniel Cho, Jae Hyun Kim, Hannah Caris, and Lev Silberstein.
This study was supported by the Burroughs Wellcome Fund and National Institutes of Health (grants 5R01DK110559, 5R01MH119459, and 1RF1AG080738).
The Biopolymers Facility Next-Gen Sequencing Core at HMS provided expertise and instrument availability for bulk RNA-seq. The Dana-Farber/Harvard Cancer Center (DF/HCC) Rodent Histopathology Core at HMS performed frozen sample sections.
Huh and Choi consult for CJ CheilJedang, hy, and Interon Laboratories. Huh is an advisor on the Samsung Biologics Advisory Board. Lu and Huh filed a provisional patent application related to this work.
