More than a decade ago, mucosal immunologist Gregory Sonnenberg had just started his own group at the University of Pennsylvania. When The Scientist spoke to him then, his research focused on a population of immune cells in the intestines called innate lymphoid cells (ILCs) and how they regulated immunity and the gut microbiome.
Shortly after this, Sonnenberg and his team identified a new subset of these cells that expressed the transcription factor retinoic acid-related orphan receptor γt (RORγt) that could present antigens to adaptive immune cells.1 In 2014, he moved to Weill Cornell Medicine where his team continued to explore these new cells and their function. “It was fun to start new areas,” he said.
Recently, Sonnenberg accepted a position at the University of California, Los Angeles (UCLA). “I'm very much looking forward to the next stage and phase of my career there,” Sonnenberg said. As The Scientist continues to celebrate its 40th anniversary, we reconnected with Sonnenberg to hear more about his research since 2013 and what he hopes this next chapter of his research career will bring.
A New Population of ILCs Leads to Revelations in Gut Immunity and Beyond
In 2013, researchers studying ILCs had shown that these innate immune cells mirrored many adaptive immune cell functions; the ILCs produced several cytokines that mediated immunity and inflammation. Because of this, Sonnenberg and his postdoctoral researcher set out to understand what made these cells unique.
This led to the pair making an unexpected discovery: one subtype of RORγt+ ILCs had antigen presentation machinery. When they knocked out the genes for this machinery from these ILCs in mice, the team saw that the animals developed a form of inflammatory bowel disease (IBD) with T cell-driven chronic inflammation in their guts. This suggested that these newly identified RORγt+ antigen presenting cells (APCs) promoted gut immune tolerance through presenting antigen to CD4+ T cells.
Reflecting on this discovery, Sonnenberg said, “It's really cool to pioneer a new field because there's so many areas you can take it, and you're the one sort of in the driver's seat deciding what's the most important thing to go after right now.”
During this work, Sonnenberg moved his team to Weill Cornell Medicine, where he met colleagues who helped his group push their findings further. Over the next decade, his group continued to explore the function of RORγt+ APCs and showed that these cells promoted regulatory T cell differentiation in the gut and how the dysregulation of these ILCs contributes to disorders like IBD.2,3
Having originally gone into biomedical science with an interest in cancer before falling in love with mucosal immunology, Sonnenberg said, “What's been exciting for me over the past decade as well is so much gut microbiome mucosal immunology research has gone into the tumor immunology field.” More recently, Sonnenberg’s team has expanded their focus to also explore how these cells influence other conditions, including colorectal cancer, airway inflammation, and multiple sclerosis.4-6
“I think the best science, the most exciting science, is incomplete and provokes you to keep asking more and more…so you can keep taking the field forward,” Sonnenberg said.
For example, today, scientists know that there are several different RORγt+ APCs, and Sonnenberg is interested in understanding each of their roles in the gut immune system.7 Additionally, new technologies like single-cell RNA sequencing and spatial transcriptomics prompted Sonnenberg to return to some of his previous findings to be able to study cell types and their functions, like gene expression and cell-cell interactions, in greater detail.
While his team conducts predominantly basic science research, Sonnenberg has kept his eye on translating the findings beyond the bench. “What's always driven me in science is seeing how it might be applicable to human health and human disease. How can we make take these findings and see [if they] are relevant in patient populations?”
To do this, Sonnenberg and his team collected biopsies from patients with IBD and assessed them for changes in RORγt+ APCs. “We have been able to show that many times now that they are fundamentally changed,” Sonnenberg said. Although these findings are only correlative in humans, he added that they “at least suggest that this dysregulation in these populations may precede or contribute to the breakdown of immune homeostasis in IBD patients and other diseases as well.”
Looking Back on and Looking Forward to New Beginnings in Research
Reflecting on his first interview with The Scientist, Sonnenberg said, “It was great to be acknowledged by [The Scientist] and to profile me for that, but also to keep giving me confidence to move forward and push forward,” he said. At the time, he had received an R01-level award from the National Institutes of Health that gave him a direct path to a professorship. He recalled how many colleagues expressed doubt about him skipping a postdoctoral position, but Sonnenberg had a clear idea for what he wanted to do in his research and trusted his gut instinct to take the risk of jumping right into a faculty position.
Now, Sonnenberg is making another career leap, having accepted a new faculty position at UCLA where he will direct the newly launched Center for Research in Inflammatory Bowel Disease. In this role, Sonnenberg is looking forward to the opportunity to build a program that can have broad impacts and support the next generation of scientists.
Sonnenberg will also be continuing his research studying gut immunity and the role of RORγt+ APCs in this site. In addition to some of the previous lines of research the team has begun from this work, Sonnenberg said, “A really exciting area has been this emerging paradigm in in connections between the nervous system and the immune system.” So far, the group has seen that many innate immune cells facilitate communication between the immune system and the nervous system, and they are eager to explore more how these interactions influence both systems and human health overall.8
“I'm really excited to see what's going to happen in this next stage and next environment and how that's going to probably continue to shape our science,” Sonnenberg said.
- Hepworth MR, et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 2013;498(7452):113-117.
- Wagage S, et al. The group 3 innate lymphoid cell defect in aryl hydrocarbon receptor deficient mice is associated with T cell hyperactivation during intestinal infection. PLoS ONE. 2015;10(5):0128335.
- Hepworth MR, et al. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria–specific CD4+ T cells. Science. 2015;348(6238):1031-1035.
- Goc J, et al. Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer. Cell. 2021;184(19):5015-5030 e16.
- Teng F, et al. ILC3s control airway inflammation by limiting T cell responses to allergens and microbes. Cell Rep. 2021;37(8):110051.
- Ma Y, et al. Epsilon toxin–producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS immune privilege. J Clin Invest. 2023;133(9):e163239.
- Abramson J, et al. The emerging family of RORγt+ antigen-presenting cells. Nat Rev Immunol. 2024;24(1):64-77.
- Grigg JB, et al. Antigen-presenting innate lymphoid cells orchestrate neuroinflammation. Nature. 2021;600(7890):707-712.
