Illuminating the Role of IL-17 in Enabling T Cells to Talk to Their Environment

Interleukin 17 (IL-17) supports protective immunity and helps to maintain healthy skin and gut. It also promotes chronic inflammation in autoimmune diseases. A University of Pittsburgh research team led by Mandy McGeachy, PhD, has found that IL-17 produced by Th17 cells promotes autoimmunity by changing the environment in the inflamed lymph node. Specifically, IL-17 signaling changes the metabolism of nonimmune stromal cells, activating them and leading them to proliferate. This ultimately supports autoantibody production.

“This is a new role for IL-17,” says Dr. McGeachy, who is an associate professor in the Division of Rheumatology and Clinical Immunology. “Most of the diseases that rheumatologists see involve a component of autoantibody as well as inflammatory T cell responses. What this study shows is that IL-17 is linking T cell response and autoantibody production by acting on nonimmune cells in the lymph nodes,” says Dr. McGeachy. The study was published in Nature Immunology in May 2019. 

Dr. McGeachy received her undergraduate degree from the University of Glasgow, Scotland, in 2001 and her doctorate from the University of Edinburgh in 2005. She completed her postdoctoral training at Schering-Plough Biopharma/Merck, formerly DNAX Research, in Palo Alto, California, where Th17 cells were first discovered. During her training, she became an expert in experimental autoimmune encephalomyelitis (EAE), a mouse model of autoimmunity. Since she joined the University of Pittsburgh in 2012, Dr. McGeachy and her colleagues have studied Th17 cells in this model and in humans to understand the biological mechanisms underlying autoimmune inflammation. 

Elucidating the Behavior of Th17 Cells

Dr. McGeachy’s laboratory has identified clues that can explain difficulties in generating human Th17 cells in vitro, defined pathogenic and regulatory Th17 cell phenotypes in autoimmune disease, and described a role for IL-23 in effector Th17 cells and autoimmune Th17 memory cells that cause disease in the brain. Now they are looking at the lymph node and spleen.

“In autoimmunity, we tend to think about blood and peripheral and target tissues, but not so much about the actual lymph node, which is where T cells are first activated,” says Dr. McGeachy.
Th17 cells start out as naïve T cells. They are activated and differentiate into Th17 cells in the lymph nodes, and they produce IL-17 as they differentiate. They also interact with nonimmune stromal cells in the lymph node. Among these cells are fibroblastic reticular cells (FRCs). Immunization or pathogen invasion trigger a series of events leading to lymphocyte retention and swelling of local lymph nodes. Activated FRCs undergo changes to support T cells, dendritic cells, and lymph transport, and they proliferate to support the expanded lymphoid tissue. Depleted or dysfunctional FRCs have been associated with secondary lymphoid fibrosis, reduced T- and B-cell viability, and impaired antiviral immunity. 

Relevant to Autoimmune Diseases

By examining the EAE model and a colitis model in wild-type mice and mice deficient in IL-17 signaling, Dr. McGeachy and her colleagues found that FRC proliferation and global antibody production both depend on a functional IL-17 receptor signaling pathway within the FRCs. When they analyzed gene expression patterns in FRCs isolated from mice deficient in IL-17 signaling, they found changes in expression for genes associated with the cell cycle, glucose uptake, aerobic glycolysis, and oxidative phosphorylation. Consistent with these findings, FRCs underwent cell cycle arrest and apoptosis, and showed signs of nutrient distress in the absence of IL-17 receptor signaling. 

Other experiments showed that IL-17 itself increased glucose uptake and mitochondrial Cpt1a expression through the transcription co-activator IκBj, which was previously known to work with NFκB to induce inflammatory cytokines. Dr. McGeachy and her colleagues concluded that IL-17 produced by differentiating Th17 cells drives FRC activation in inflamed lymph nodes by reprogramming FRC metabolism. They will explore these effects further in tissues where disease occurs, both in mouse models and in humans.

“Understanding how the immune system metabolically activates stromal cells is a fairly new area within immunology,” says Dr. McGeachy. “This is relevant to most autoimmune diseases because in any tissue site you have resident cells and immune cells speaking to each other. IL-17 always acts on nonimmune cells. In rheumatoid arthritis, it activates synovial stromal cells to drive inflammation in the joint. In the skin, it activates keratin to drive inflammation during psoriasis or psoriatic arthritis. Now we’ve found that IL-17 is acting on nonimmune cells in the lymph nodes.”

A Collaborative Environment

The U.S. Food and Drug Administration has approved several biologic therapies targeting IL-17 or its receptor for psoriasis, psoriatic arthritis, and ankylosing spondylitis. These therapies have become the new gold standard in psoriasis treatment, and they work just as well in psoriatic arthritis and ankylosing spondylitis. The results of clinical trials in other inflammatory diseases, however, have been more disappointing. 

“Some rheumatologists might think IL-17 is not important or that it’s only important in mouse studies,” says Dr. McGeachy. “They assume it doesn’t work for these diseases. But there is pretty good evidence for IL-17 in rheumatoid arthritis and other rheumatology-related diseases that hasn’t been tested yet. When you examine the data, it appears to work in a subset of patients.”

Dr. McGeachy credits a collaborative environment at UPMC and the University of Pittsburgh for bringing this and other studies in her lab to fruition. While her laboratory focuses primarily on the interactions between Th17 cells and nonimmune cells, Dr. McGeachy and her team explored IL-17 signaling and metabolic changes in collaboration with Sarah Gaffen, PhD, the Gerald P. Rodnan Endowed Professor of Medicine in the Division of Rheumatology and Clinical Immunology, and Greg M. Delgoffe, PhD, assistant professor in the Department of Immunology at the University of Pittsburgh. Dr. McGeachy and Dr. Gaffen also have published several studies on IL-17 signaling in autoimmunity and infections. 

Incorporating a Translational Focus

Through interactions with clinicians at UPMC, and with access to patient samples, Dr. McGeachy’s laboratory has incorporated a translational focus into its work. This translational aspect is bidirectional, says Dr. McGeachy. Collaboration enables her laboratory not only to translate mouse findings into human studies but also to use findings from human studies to validate and optimize mouse models. The laboratory is now exploring FRCs from human tonsils and expanding its focus into other diseases.

“The next arm of this work is considering the extent to which the change in metabolism and the ramping up of the energy capability of the stromal cells are happening in the connective tissues where disease is occurring,” says Dr. McGeachy. “Is IL-17 driving the pathways that promote increased metabolism that in turn allow inflammation and pathologic proliferation?  Because in a lot of rheumatic diseases, what’s happening is overextension of populations of cells that are not helpful and that then cause more inflammation and contribute to the disease. This is one of the areas where I think this work will lead that will have more direct translational relevance.”

Dr. McGeachy and her study collaborators were supported by grants from the National Institutes of Health, the Richard King Mellon Institute for Pediatric Research, and the American Association for Cancer Research, as well as by resources from the University of Pittsburgh Center for Research Computing.

References

Majumder S, Amatya N, Revu S, Jawale CV, Wu D, Rittenhouse N, Menk A, Kupul S, Du F, Raphael I, Bhattacharjee A, Siebenlist U, Hand TW, Delgoffe GM, Poholek AC, Gaffen SL, Biswas PS, McGeachy MJ. IL-17 Metabolically Reprograms Activated Fibroblastic Reticular Cells for Proliferation and Survival. Nat Immunol. 2019 May; 20(5): 534-545. doi: 10.1038/s41590-019-0367-4. 

Further Reading

McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 Family of Cytokines in Health and Disease. Immunity. 2019 Apr 16; 50(4): 892-906. doi: 10.1016/j.immuni.2019.03.021. Review.

Verma AH, Zafar H, Ponde NO, Hepworth OW, Sihra D, Aggor FEY, Ainscough JS, Ho J, Richardson JP, Coleman BM, Hube B, Stacey M, McGeachy MJ, Naglik JR, Gaffen SL, Moyes DL. IL-36 and IL-1/IL-17 Drive Immunity to Oral Candidiasis via Parallel Mechanisms. J Immunol. 2018 Jul 15; 201(2): 627-634. doi: 10.4049/jimmunol.1800515.