A $13.3 million grant from the National Institutes of Health will support a Cornell-led effort to reveal the long-standing mystery of how immune cells communicate within living tissues across time and space, which could shape new approaches for treating inflammatory diseases, autoimmune disorders and infections.

The five-year program project grant will bring together immunologists, engineers and computational scientists from Cornell and the University of Rochester Medical Center, and combine advanced imaging and spatial genomics technologies allowing researchers to observe immune responses in unprecedented detail.

Immune responses are dynamic and highly localized, and traditional approaches to immunology research – such as blood samples or biopsies – often fail to capture immune activity where it is actually occurring, said Deborah Fowell, professor and chair of microbiology and immunology in the College of Veterinary Medicine and director of the Cornell Center for Immunology, who will lead the project.

“The program focuses on understanding immune responses in tissues using cutting-edge tools that enable us to visualize immune responses in real-time in inflamed sites,” she said. “By studying these interactions across both time and space, we hope to uncover new principles governing immune function and identify opportunities for new therapies.”

Immune cells organize into specialized “niches” within tissues, where they exchange signals that shape inflammation, infection responses, tissue repair and immune memory. To observe those interactions, Fowell explained, researchers will use two- and three-photon intravital microscopy, imaging technologies pioneered at Cornell, that allow them to track immune-cell behavior deep within living tissues, including lymph nodes, skin and lung. It will be paired with spatial transcriptomics, which measures gene activity while preserving information about where cells are located within a tissue.

“An immune response is an orchestrated event that involves specific immune cells and unfolds in specific places and at specific times within a tissue,” said Iwijn De Vlaminck, professor of biomedical engineering in the Cornell Duffield College of Engineering and director of the project’s Spatial Transcriptomics Core. 

“Spatial transcriptomics lets us view three dimensions of measurement at once – cellular identity, immune receptor specificity and location – so we can watch which immune cells act where within the native tissue architecture,” he said. “More conventional approaches, such as imaging or single-cell sequencing, capture one or two of these dimensions but not all three together, and so they miss key information about how the response is organized.” 

The program incorporates a fourth dimension, time, through real-time imaging.  Toggling back and forth between high resolution dynamic images and the molecular program provides the unique ability to dissect in situ, in their natural context, the signals that drive and regulate immune function, Fowell said. 

In collaboration with Fowell, research projects will be led by Mandy McGeachy and Brian Rudd in the Department of Microbiology and Immunology in CVM, and by Minsoo Kim at the University of Rochester Medical Center. 

Supporting the research are two technology innovation hubs or “cores” that provide advanced facilities and expertise used across all four research projects. Along with De Vlaminck’s management of spatial transcriptomics in support of the project, a specialized imaging core will be directed by Chris Xu, professor of applied and engineering physics, with Nozomi Nishimura, associate professor of biomedical engineering, and Chris Schaffer, professor of biomedical engineering, serving as co-directors, all from Duffield Engineering.

“Cross-university collaboration between immunologists and engineers enables the immune response to be studied at extraordinary resolution,” Fowell said. “We couldn’t begin to ask these novel immunological questions without the groundbreaking tools developed by our engineering colleagues.”

The grant was first awarded to Fowell in 2014 while she was at the University of Rochester and has now been renewed for a third five-year funding period. Since joining Cornell in 2020, Fowell has expanded the program to include new investigators from microbiology and immunology, biomedical engineering and applied and engineering physics.

Earlier this year, researchers from the Fowell, Rudd and De Vlaminck laboratories published findings in the Proceedings of the National Academy of Sciences demonstrating how to link spatial gene-expression data with immune-cell identity and function. The newly funded program will build on this foundation.

The NIH grant also includes support for seed grants fostering the development of next-generation tools for studying immune responses, and a biennial Immune Imaging Symposium that will bring leading researchers from around the world to Cornell. These will be supported by CVM and Duffield Engineering. 

“This project exemplifies the power of collaboration across disciplines,” said Gary Koretzky, vice provost for research. “Cornell’s greatest strengths emerge when researchers from different fields work together to tackle complex scientific challenges. By bringing together expertise in immunology, engineering and computational biology, this program creates opportunities for discoveries that would not be possible within a single discipline.”

Stephen D'Angelo is the communications manager for biological systems at Cornell Research and Innovation.