Gut Commensal Segmented Filamentous Bacteria Fine-Tune T Follicular Regulatory Cells to Modify the Severity of Systemic Autoimmune Arthritis

Abstract

Autoantibodies play a major pathogenic role in rheumatoid arthritis. T follicular helper (Tfh) cells promote germinal center B cell and Ab responses. Excessive Tfh cell responses lead to autoimmunity, and therefore, counterregulation is crucial. T follicular regulatory (Tfr) cells, mainly differentiated from T regulatory cells, can negatively regulate Tfh and germinal center B cells. Dysbiosis is involved in rheumatoid arthritis's pathogenesis. We previously demonstrated that the gut microbiota, segmented filamentous bacteria (SFB), promote autoimmune arthritis by inducing Tfh cells. However, little is known regarding whether gut microbiota influence systemic (nongut) Tfr cells, impacting gut-distal autoimmunity. In this study, using SFB in autoimmune arthritic K/BxN mice, we demonstrated that SFB-induced arthritis is linked to the reduction of Tfr cells' CTLA-4, the key regulatory molecule of Tfr cells. This SFB-mediated CTLA-4 reduction is associated with increased Tfr glycolytic activity, and glycolytic inhibition increases Tfr cells' CTLA-4 levels and reduces arthritis. The surface expression of CTLA-4 is tied to TCR signaling strength, and we discovered that SFB-reduced CTLA-4 is associated with a reduction of Nur77, an indicator of TCR signaling strength. Nur77 is known for repressing glycolytic activity. Using a loss-of-function study, we demonstrated that Nur77 +/2 haplodeficiency increases glycolysis and reduces CTLA-4 on Tfr cells, which is associated with increased arthritis and anti-glucose-6phosphate isomerase titers. Tfr-specific deletion (KRN.Foxp3CreBcl-6 fl/fl ) in autoimmune condition reveals that Tfr cells repress arthritis, Tfh cells, and autoantibody responses and that SFB can mitigate this repression. Overall, these findings demonstrated that gut microbiota distally impact systemic autoimmunity by fine-tuning Tfr cells.

Mechanism of Immunoregulatory Properties of Vasoactive Intestinal Peptide in the K/BxN Mice Model of Autoimmune Arthritis

“…This is compatible with the decreased Th17 cell population and increased Tfh cell population seen in the K/BxN model occurring during ageing, which also depends on the gut microbiota. Very recently, gut microbiota has been shown to influence systemic Tfr cells, impacting systemic autoimmunity in the present animal model of autoimmune arthritis (59). This means the implication of the local microbiota and nervous circuits in the regulation of autoimmune diseases.…”

Critical role of the gut microbiota in immune responses and cancer immunotherapy

“…Some Treg cells are also found in B-cell follicles and were identified as T follicular regulatory (Tfr) cells. These cells can migrate into the GC, thereby inhibiting B-cell maturation and antibody production [ 163 ] SFB, which induces Tfh cells to promote autoimmune arthritis, has also exhibited the potential to influence systemic Tfr cells [ 164 ]. In addition, butyrate is an environmental cue that can induce the differentiation of Tfr cells, which can also ameliorate autoimmune arthritis [ 165 ].…”

Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy

“…Other notable bacterial shifts in the gut microbiota for RA patients include a bloom in Proteobacteria, Clostridium cluster XlVa, and Ruminococcus, which were correlated with less CD4 + T cells and Treg cells [348]. Using the K/BxN autoimmune arthritis model, it was found that SFB-mediated cytotoxic T lymphocyte antigen-4 (CTLA-4) reduction caused autoreactive T follicular helper cells [349,350]. The accumulation of T follicular helper cells and Th17 cells in arthritis appears to be age-dependent [351], which helps to explain why RA is found mostly in the older population.…”