Gut Microbiota Drive Autoimmune Arthritis by Promoting Differentiation and Migration of Peyer’s Patch T Follicular Helper Cells

Abstract

SUMMARY 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.

Segmented Filamentous Bacteria Provoke Lung Autoimmunity by Inducing Gut-Lung Axis Th17 Cells Expressing Dual TCRs

“…We previously established a model to study the effect of SFB in autoimmune development by gavaging SFB-containing (simplified as SFB+ hereafter) feces into SFB negative (SFB−) mice housed in our specific-pathogen-free animal facility (Teng et al, 2016). Arthritis development plateaus on or beyond day 14 post-SFB gavage in this model.…”

“…The low concordance rate of RA in monozygotic twins (~20%) suggests that environmental factors play a key role in RA (Seldin et al, 1999). We have previously demonstrated that the gut microbiota, segmented filamentous bacteria (SFB), act as an environmental cue to enhance autoimmune arthritis by inducing T helper 17 (Th17) and T follicular helper (Tfh) cells (Teng et al, 2016; Wu et al, 2010). A strong interest has emerged in characterizing the role of gut microbiota in lung disease, a gut-lung axis of communication, exemplified by gut microbiota’s impact on diseases including asthma, chronic obstructive pulmonary disease (COPD), and respiratory infections (Budden et al, 2017).…”

Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice

“…For example, SFB colonization promotes disease in the K/BxN mouse model of RA, in part by inducing SI-LP Th17 cells that emigrate from the gut to the spleen, where they promote production of autoantibodies against glucose-6-phosphate isomerase (24,41). Such autoantibodies in and of themselves can induce arthritis and, after they reach high levels, require no further input from Th17 cells.…”

Do the Microbiota Influence Vaccines and Protective Immunity to Pathogens?

“…Although the T H 17 cells induced by SFB are noninflammatory, in the right major histocompatibility complex (MHC) background of autoimmune predisposition, they can provide help for B-cell-dependent autoimmune arthritis. susceptibility, the SFB T H 17 subset can provide the necessary germinal center help to generate arthritis via autoantibodies (Maloy et al 2003;Wu et al 2010;Teng et al 2016). Given the local focus of most mucosal immune responses induced by the microbiota, the most promising opportunities are to use these responses to manipulate the system to dampen proinflammatory responses from its more aggressive members.…”