Immune Dictionary Reveals Deepest-Yet View into Workings of the Immune System

The immune system plays an essential role in keeping us healthy and in protecting us from disease. Immune cells are regulated by cytokines, key molecules (of which there are more than 100 major types) that send chemical messages that dictate how and when immune cells develop or activate against threats to our health. Cytokines are so critical to the function of the immune system that more than one million scientific publications have studied them — yet until now there’s been no systemic reference for understanding how specific cytokines affect different types of immune cells.

 

Researchers from the Broad Institute, Harvard University, and Massachusetts Institute of Technology have bridged this gap by unveiling a first-of-its-kind Immune Dictionary, mapping out precisely how 86 cytokines activate genes that control the state and function of more than 17 types of immune cells. The landmark study, which details immune system responses at the single-cell and single-cytokine level, was published in Nature.

 

“The field of chemistry has the periodic table of elements, and the field of genomics has the Human Genome Project reference sequence,” says Ang Cui, lead and co-corresponding author on the paper, who is a member of the faculty in Oral Medicine, Infection, and Immunity and director of the Systems Immunology Research Lab at Harvard School of Dental Medicine. “However, such a reference has been missing in the field of immunology, limiting our ability to understand the complex immune system in a precise manner and develop more effective immunotherapies.”

 

Cui and collaborators at the Broad Institute, where she was formerly a graduate fellow in Harvard-MIT Health Sciences and Technology and postdoctoral researcher in the lab of co-corresponding senior author Nir Hacohen, designed the Immune Dictionary to be a comprehensive and open-access reference of immune responses.

 

“Our study looked at nearly all major immune cell types responding to nearly all of the major cytokines,” Hacohen says. “With more than 1,400 cytokine-cell type combinations, we now have a more global view of cytokine actions and a map for the field to use.”

 

They used single-cell RNA sequencing to examine how each type of immune cell in the lymph nodes of mice reacted to the introduction of 86 different cytokines. Their cell-by-cell analysis revealed how the introduction of any given cytokine changed the activity of each gene of each immune cell type.

 

 

Now “anyone can look up the Immune Dictionary to understand how a cytokine affects gene expression in any immune cell type,” Cui says.

 

The team also developed companion software called Immune Response Enrichment Analysis (IREA), allowing other scientists to leverage the Immune Dictionary to pinpoint which cytokines are most central to certain diseases or therapeutic responses. IREA is freely available online.

 

“In the past, experiments to understand cytokine effects in each disease could take months to years,” Cui says. “The IREA software can obtain predictions within minutes because it simply needs to compare a user’s experimental data with the Immune Dictionary. Based on the IREA software prediction, scientists can propose a design for therapies to enhance or block a specific cytokine for treating each disease.”

 

Cytokines can be exploited or blocked to treat patients with autoimmune disorders, COVID-19 and other viral infections, tumors, allergies, cardiovascular and neurodegenerative diseases, and more. Inflammatory cytokines play a critical role in both oral and systematic diseases, significantly impacting the overall well-being of every individual.

 

“There have been studies on how immune cells respond to a handful of cytokines in a dish, but the body’s responses to cytokines are much more complex,” Cui says. “Our study measures the immune responses in a physiological setting to understand how cells of the body respond to cytokines.”

 

While developing the Immune Dictionary, Cui and her team encountered some startling observations. “There are likely new functions of immune cells that have not been known before,” she says. They learned that immune cells are surprisingly plastic, or able to shift their behavior depending on the instructions that cytokines deliver. And they saw that a single cytokine is sufficient for orchestrating a sophisticated immune response.

 

Cui, Hacohen, and their collaborators hope the Immune Dictionary and IREA software will be used by scientists studying many diseases to better understand how specific cytokines are contributing to disease states. They also hope their tools can be used for personalized medical approaches, analyzing data from individuals to see how each person’s unique makeup reacts to vaccines or medicines.

 

— Kat J. McAlpine, HSDM Correspondent

 

This work was supported by the National Institute of Health, Adelson Medical Research Foundation, Natural Sciences and Engineering Research Council of Canada, MIT Whitaker Health Sciences Fund, MIT Wellington and Irene Loh Fund, and MIT Undergraduate Research Opportunities Program.