RT Journal Article
SR Electronic
T1 Gut Commensal Segmented Filamentous Bacteria Fine-Tune T Follicular Regulatory Cells to Modify the Severity of Systemic Autoimmune Arthritis
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP ji2000663
DO 10.4049/jimmunol.2000663
A1 Bates, Nicholas A.
A1 Li, Anna
A1 Fan, Tingting
A1 Cutcliffe, Madeline P.
A1 Dagenet, Caitlyn B.
A1 Sleiman, Kiah C.
A1 Ma, Heqing
A1 Tahsin, Shekha
A1 Garrett, Candace S.
A1 Altemus, Jesse
A1 Wu, Hsin-Jung Joyce
YR 2021
UL http://www.jimmunol.org/content/early/2021/01/17/jimmunol.2000663.abstract
AB SFB-mediated CTLA-4 reduction is associated with increased Tfr glycolytic activity.Reduced Nur77, an indicator of TCR signal strength, is linked to SFB-reduced CTLA-4.Nur77 deficiency causes an increased glycolysis and decreased CTLA-4 in Tfr cells.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+/− haplodeficiency increases glycolysis and reduces CTLA-4 on Tfr cells, which is associated with increased arthritis and anti–glucose-6-phosphate isomerase titers. Tfr-specific deletion (KRN.Foxp3CreBcl-6fl/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.