Gut Microbiota Drive Autoimmune Arthritis by Promoting Differentiation and Migration of Peyer's Patch T Follicular Helper Cells.
Gut microbiota profoundly affect gut and systemic diseases, but the mechanism whereby microbiota affect systemic diseases is unclear. It is not known whether specific microbiota regulate T follicular helper (Tfh) cells, whose excessive responses can inflict antibody-mediated autoimmunity. Using the K/BxN autoimmune arthritis model, we demonstrated that Peyer's patch (PP) Tfh cells were essential for gut commensal segmented filamentous bacteria (SFB)-induced systemic arthritis despite the production of auto-antibodies predominantly occurring in systemic lymphoid tissues, not PPs. We determined that SFB, by driving differentiation and egress of PP Tfh cells into systemic sites, boosted systemic Tfh cell and auto-antibody responses that exacerbated arthritis. SFB induced PP Tfh cell differentiation by limiting the access of interleukin 2 to CD4(+) T cells, thereby enhancing Tfh cell master regulator Bcl-6 in a dendritic cell-dependent manner. These findings showed that gut microbiota remotely regulated a systemic disease by driving the induction and egress of gut Tfh cells.
Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA.
Fei
F
Teng
Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA.
Christina N
CN
Klinger
Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA.
Krysta M
KM
Felix
Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA.
C Pierce
CP
Bradley
Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA.
Eric
E
Wu
Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA.
Nhan L
NL
Tran
Yakult Central Institute, Izumi 5-11, Kunitachi, Tokyo, Japan.
Yoshinori
Y
Umesaki
Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA; Arizona Arthritis Center, College of Medicine, University of Arizona, Tucson, AZ 85719, USA. Electronic address: joycewu@email.arizona.edu.
Hsin-Jung Joyce
HJ
Wu
D000818:Animals; D001168:Arthritis / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology*; D051560:Proto-Oncogene Proteins c-bcl-6; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*
D001323:Autoantibodies; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D051560:Proto-Oncogene Proteins c-bcl-6; D011948:Receptors, Antigen, T-Cell