Scientists first reported in 2016 that specific gut microbes known as commensal bacteria, which cause no harm and often contribute to host health, set off production and release of a gut-originated T cell that drives up body-wide autoimmune disease in mice. Since then, the team has focused on explaining this unexpected twist in the typically harmonious relationship between these microbes and the body.
The gut is where the action begins, but the overall outcome can be attributed to T cells’ “plasticity” – their flexibility to respond to a changing environment, such as in our body’s barrier, the gut.
In this case, reprogrammed T helper cells adopt characteristics of a new T helper cell type while preserving some of their original traits, making them “super powerful and potent – and if you are dealing with autoimmune disease, that’s bad news,” said senior study author Hsin-Jung Joyce Wu, professor of internal medicine, division of rheumatology and immunology, at The Ohio State University College of Medicine.
“This is really the first time it’s been shown that T cell plasticity, which typically occurs in the gut, can have this dramatic impact outside the gut with systemic impact on autoimmune disease.”
The findings likely have relevance to human patients, Wu said: Many of the gene expressions detected in these abnormal cells in mice also exist in the same cells in people with rheumatoid arthritis.
The research was published April 30 in Nature Immunology.
An estimated 18 million people worldwide are affected by rheumatoid arthritis (RA), a chronic autoimmune disease causing inflammation throughout the body and pain in the joints. Like other autoimmune diseases, RA is caused by the immune system attacking the body’s tissues and organs. Though the exact cause is unknown, genetics and environmental exposures – such as smoking and changes of gut commensal bacteria, or dysbiosis – are among the risk factors.
The abnormal T cell in question is called a T follicular helper 17 (TFH17) cell – meaning it functions as a TFH cell but also displays T helper 17 (TH17) cell signatures. Several previous studies have reported that the human equivalent of these types of cells are found in the blood of patients with autoimmune diseases, and are linked to more severe symptoms, but little has been known about the cells’ backstory.
These cells have been a puzzle, Wu said, because the conventional TFH cells are expected to be nonmobile, and just reside in B cell follicles to help B cells, another immune cell type critical for the development of RA. But unlike conventional TFH cells, the TFH17 cells also have the traveling capabilities of T helper 17 cells, which are known to migrate rapidly to infection sites where they produce a proinflammatory protein called IL-17.
Following their 2016 study, Wu’s lab has now discovered that the systemic TFH cells traced back to Peyer’s patches, lymphoid tissue in the small intestine, and induced by typically harmless microbes called segmented filamentous bacteria, are enriched with TFH17 cells.
More specifically, fate-mapping mouse models showed that the hybrid cells derived from T helper 17 (TH17) cells in the gut transformed into T follicular helper cells inside Peyer’s patches, and that the segmented filamentous bacteria enhanced the cell reprogramming process.
“The key is T cell plasticity only happens in very few places, which is why it’s been overlooked – the dominant place to find them is in the gut barrier,” Wu said. “And that’s one of few places in the body where the environment can change from one second to the next, and therefore induction of T cell plasticity occurs to accommodate the ever-changing environmental challenge.”
The team then used fluorescent tagging of cells in the arthritic mouse model to observe the cells’ movement from the gut to the rest of the body.
“That’s how we knew they were really traveling,” Wu said. Importantly, these cells also acquire a stronger capability to help B cells compared to conventional TFH cells.
“That’s what makes them ultra-pathogenic TFH cells in RA, a systemic disease, because they are very mobile and can potently help B cells,” she said.
To demonstrate the hazard associated with these abnormal TH17-derived TFH cells, researchers compared RA development in genetically susceptible mouse models injected with only conventional TFH cells (control group) or conventional TFH cells mixed in with around 20% of TH17-derived TFH cells.
Substituting a small number of the conventional cells with these aberrant TFH cells increased the arthritis-related ankle thickening in mice by 4.8-fold compared to control mice, a finding that took Wu and colleagues by surprise.
Researchers also sequenced the gene expression profiles of the aberrant T follicular helper cells isolated from the gut of RA mouse models and found that they shared several similarities with those of TFH cells circulating in the blood of people with RA – including the gut signature, hinting that a similar mechanism is behind human disease as well.
“That, to me, was exciting, to find this cross-species signature, which suggests the translational potential of this research,” Wu said. “We are hoping to improve patients’ health and life. For the future, as TFH17 cells can be found in other type of autoimmune patients, such as lupus patients, if we can determine that these abnormal TFH cells are a potential target not just for RA, but across autoimmune diseases, that would be very useful.”
This work was supported by the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute.
Co-authors include Tingting Fan, Chi Tai, Madeline Cutcliffe, Haram Kim, Ye Liu, Jianying Li, Gang Xin, Mollyanna Grashel, Laurie Baert, Chinwe Ekeocha, Paige Vergenes, Judith Lin, Beatriz Hanaoka and Wael Jarjour of Ohio State; Kiah Sleiman and Trevor Tankersley of the University of Arizona; Svetlana Lima and Randy Longman of Weill Cornell Medicine; Wan-Lin Lo of the University of Utah; Min Wang and Xuan Zhang of the National Center of Gerontology in Beijing; and George Tsokos of Harvard Medical School.
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Contact: Hsin-Jung Joyce Wu, Joyce.Wu@osumc.edu
Written by Emily Caldwell, Caldwell.151@osu.edu; 614-292-8152
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