An estimated 18 million people worldwide are affected by rheumatoid arthritis (REA), a chronic autoimmune disease causing inflammation throughout the body and pain in the joints. Like other autoimmune diseases, REA 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. Basically, there is an abnormal response of T cells or lymphocytes to autoantigens, like happens in other autoimmune conditions. 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, because the conventional TFH cells are expected to be nonmobile, and just reside in B cell follicles to help B lymphocytes, the immune cell type critical for the development of auto-antibodies in REA. 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 cytokine 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 team therefore used fluorescent tagging of cells in the arthritic mouse model to observe the cells’ movement from the gut to the rest of the body. 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 REA because they are very mobile and can potently help B cells. 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 scientists by surprise. By gene expression profiles of the aberrant T follicular helper cells isolated from the gut of RA mouse models, scientists found that they shared several similarities with those of TFH cells circulating in the blood of people with REA.
Thus, gut T cell plasticity generates atypical, potent TFH cells promoting systemic autoimmunity. Since most of priomary immune responses start in the gut with the cooperation of resident host (the microbiota), these informations furtherly enhances the role fo gut dysbiosis as possible spark or contributor to REA pathogenesis.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Fan T et al. Nat Immunol. 2025 May; 26(5):790-804.
Bates NA et al. J Immunol. 2021; 206(5):941-952.
Teng F et al. Immunity. 2016 Apr 19; 44(4):875-88.
