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Florent Ginhoux, Senior Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN)

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Tracing immune cells to their source

20 Dec 2021

New research techniques are enabling scientists like SIgN’s Florent Ginhoux to unravel the complexities of the immune system like never before.

If you have been fortunate enough to have received a vaccine against SARS-CoV-2, the protection you now enjoy is in no small part due to a specific kind of immune cell: the dendritic cell (DC).

Named for their many-branched protrusions, DCs take up foreign antigens like the SARS-CoV-2 spike protein, digest them into smaller fragments and then present them to cells of the adaptive immune system such as B cells and T cells. This interaction causes the adaptive immune cells to mature into antibody-producing cells or cytotoxic cells capable of killing virus-infected cells, thus protecting the host from subsequent infection.

First discovered in 1868 and originally classified as skin nerve endings, Langerhans cells certainly look the part—with long projections that make them resemble nerve cells. However, in the 1980s, these cells were subsequently reclassified as a type of DC. Later on, pioneering work by Miriam Merad of Mount Sinai School of Medicine (MSSM) revealed that Langerhans cells are actually macrophages, a different, though closely related type of cell with embryonic origins.

The origins of these different types of immune cells have implications for their functions, affecting everything from the body’s ability to fight off infections to the ability of tumors to hide from the immune system. Fascinated by the dual nature of Langerhans cells, which have macrophage origins but dendritic cell-like behavior, Florent Ginhoux—currently a Senior Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN)—joined Merad’s laboratory after his PhD studies at the Pierre and Marie Curie University.

An early career puzzle

That decision proved to be a pivotal turning point. In Merad’s laboratory, Ginhoux found not only an excellent supervisor but also an inspiring mentor. “She transformed me in terms of being more ambitious and positive; her enthusiasm and passion for her work was infectious,” recalled Ginhoux.

Merad’s findings that Langerhans cells are maintained in the tissue by cells with embryonic origins challenged the existing consensus that all immune cells originate from precursors in the bone marrow. This finding also prompted the reclassification of Langerhans cells from DCs to macrophages.

Curious as to whether other types of macrophages also bucked the bone marrow trend, Ginhoux turned his attention to microglia, a specialized macrophage found in the brain. In a 2010 paper published in Science, Ginhoux and his collaborators discovered that—like Langerhans cells—microglia, too, had primitive origins.

“This paper changed my career but also changed the field in terms of how people viewed the origin of macrophages,” revealed Ginhoux. “I capitalized on this discovery and used it to build up my lab in Singapore.”

Finding a niche

In 2009, Ginhoux moved to Singapore, joining SIgN as a Junior Principal Investigator. At the time, SIgN was a new research institute with an energetic buzz that drew him into the community, he said. “This, along with very early and significant support from A*STAR in terms of research funding, manpower and environment were the key things that made me successful in Singapore.”

Armed with emerging technologies like single-cell mRNA sequencing and multidimensional flow cytometry, Ginhoux’s lab was able to build on his earlier findings on macrophages. One of their key contributions was the discovery that location-specific cues have an enormous impact on macrophage phenotype, shaping the specialization and function of macrophages in different tissues.

Ginhoux also continued to delineate the origins of DCs in humans, describing new steps of the cells’ differentiation by identifying DC precursors (pre-DCs) circulating in the blood. These surprising findings were made possible by high-dimensional techniques such as cytometry by time-of-flight (CyTOF), giving the researchers unprecedented insight into complex cell surface markers.

“High-dimensional profiling using single-cell and RNA sequencing has been a launching pad for many of our papers. The next step for us is to integrate this data with other dimensions such as epigenetics,” said Ginhoux. “In addition, for us, we are moving towards spatial profiling.”

Back in the days when Langerhans cells were first discovered, scientists could only look at cells under a microscope slide, studying at most two parameters. The first revolution came with the advent of flow cytometry, which allowed scientists to study many parameters at once, on cells that were made into a suspension. However, because cells were treated as individual units, flow cytometry did not give spatial information such as which other cells were in close proximity.

“Spatial profiling will allow you to not only identify different populations with different markers but also to know where they are in the tissue and how they interact with other cells. As there are many sub-tissue niches, it is very important to understand how cells touch and communicate,” explained Ginhoux.

Training for the future

Amidst the steady stream of research and high-impact publications emerging from Ginhoux’s laboratory, it comes as no surprise that keeping up with immunology’s most recent developments is a must for his students.

“I'm very hopeful—but also sometimes positively mind-blown and a bit overwhelmed—by the amount of data coming out of research labs around the world. It’s almost impossible to follow, digest and integrate all the latest technologies,” said Ginhoux. “I push my students to not only be good biologists but also integrate skills like bioinformatics.”

Students and mentees alike attest to his commitment to both rigor and intellectual curiosity. “Our ideas come first and foremost from a strong foundation in the fundamental concepts of immunology and a strong grasp of the current consensus of the field,” said Christopher Lee, a PhD candidate from the Ginhoux’s lab. “We are always encouraged to avoid reading our biases and preferences into the data, but to instead look at where the data is leading us.”

One area of research that the data is leading the lab towards is the field of stem cells. In 2017, the team showed that it is possible to generate human macrophages from induced pluripotent stem cells, paving the way for future therapeutic use and better modeling of human diseases. “We want to keep up this momentum, implementing the latest technology to address diseases like cancer and Alzheimer’s disease,” noted Ginhoux.

With his track record and commitment to scientific inquiry, Ginhoux is likely to succeed. “Florent has a strong scientific vision and the unique ability to have both a high-level view on the overall impact of a problem and a granular view on what’s the best experimental approach to address the problem,” concluded Merad. “He is just made to be a scientist.”

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References

1. Merad, M., Manz, M.G., Karsunky, H., Wagers, A., Peters, W., et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nature Immunology 3, 1135–1141 (2002).
2. Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841-845 (2010).
3. Chakarov, S., Lim, H.Y., Tan, L., Lim, S.Y., See, P., et al. Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science 363, eaau0964 (2019).
4. See, P., Dutertre, C-A., Chen, J., Gunther, P., McGovern, N., et al. Mapping the human DC lineage through the integration of high-dimensional techniques. Science 356, eaag3009 (2017).
5. Takata, K., Kozaki, T., Lee, C.Z.W., Thion, M.S., Otsuka, M., et al. Induced-pluripotent-stem-cell-derived primitive macrophages provide a platform for modeling tissue-resident macrophage differentiation and function. Immunity 47, 183-198 (2017).

About the Researcher

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Florent Ginhoux

Senior Principal Investigator

Singapore Immunology Network (SIgN)
Florent Ginhoux is Senior Principal Investigator at the Singapore Immunology Network (SIgN), A*STAR. He obtained his PhD in 2004 from the University Pierre et Marie Curie, Paris VI. As a postdoctoral fellow, he joined the Laboratory of Miriam Merad in the Mount Sinai School of Medicine (MSSM), New York, where he studied the ontogeny and the homeostasis of cutaneous dendritic cell populations, with a strong focus on Langerhans cells and Microglia. In 2008, he became an Assistant Professor in the Department of Gene and Cell Medicine, MSSM and member of the Immunology Institute of MSSM. He joined SIgN in May 2009 as a Principal Investigator before becoming Senior Principal Investigator in 2017. He has been a Web of Science Highly Cited Researcher since 2016, and an EMBO member since 2022. Ginhoux is also an Adjunct Visiting Associate Professor in the Shanghai Immunology Institute, Jiao Tong University, as well as Adjunct Associate Professor in the Translational Immunology Institute, SingHealth and Duke NUS. He is now a laboratory director in Gustave Roussy Hospital, Villejuif, France. His new laboratory focuses on paediatric cancers.

This article was made for A*STAR Research by Wildtype Media Group