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

Abstract

SUMMARY Lung complications are a major cause of rheumatoid arthritis-related mortality. Involvement of gut microbiota in lung diseases by the gut-lung axis has been widely observed, but the underlying mechanism remains mostly unknown. Using an autoimmune arthritis model, we show that a constituent of the gut microbiota, segmented filamentous bacteria (SFB), distantly provoke lung pathology. SFB induce autoantibodies in lung during the pre-arthritic phase, and SFB-dependent lung pathology requires the T helper 17 (Th17) responses. SFB-induced gut Th17 cells are preferentially recruited to lung over spleen due to robust expression in the lung of the Th17 chemoattractant, CCL20. Additionally, we found that in peripheral tissues, SFB selectively expand dual T cell receptor (TCR)-expressing Th17 cells recognizing both an SFB epitope and self-antigen, thus augmenting autoimmunity. This study reveals mechanisms for commensal-mediated gut-lung crosstalk and dual TCR-based autoimmunity.

Response to Fungal Dysbiosis by Gut-Resident CX3CR1+ Mononuclear Phagocytes Aggravates Allergic Airway Disease

“…We anticipate that there are additional factors and immune cell networks downstream of CX3CR1 + MNPs that may contribute to the effect of gut fungal dysbiosis on AAD. A recent study has indeed demonstrated that lung autoimmune inflammation can be triggered by segmented filamentous bacteria gut-lung axis Th17 cell induction (Bradley et al, 2017). While our study exploring the innate immune events affecting lung allergy during gut fungal dysbiosis, it will be important for future studies to determine how adaptive antifungal responses generated upon CX3CR1 + MNP activation affect systemic and distal site immunity.…”

“…While our study exploring the innate immune events affecting lung allergy during gut fungal dysbiosis, it will be important for future studies to determine how adaptive antifungal responses generated upon CX3CR1 + MNP activation affect systemic and distal site immunity. Gut–lung axis migration of T cells, innate lymphoid cells or inflammation-related factors have been shown to occur (Bradley et al, 2017; Huang et al, 2018; Kim et al, 2014) and could be possible avenues to pursue in future studies investigating the role of fungal dysbiosis on peripheral immunity and inflammatory diseases at gut distal sites.…”

Adaptive immune education by gut microbiota antigens

“…SFB‐specific Th17 cells are found in the peripheral lymphoid organs beyond the intestine, which could potentially contribute to the vulnerability to some autoimmune diseases in genetically susceptible hosts . In addition to previously proposed molecular mimicry and bystander activation theories as to the mechanism for microbiota‐reactive T cells to trigger autoimmunity, a recent study in a lung autoimmune mouse model showed that SFB selectively expanded Th17 cells that expressed dual TCR, one of which recognized SFB peptide and the other directed at a self‐antigen …”

The microbiota and immune‐mediated diseases: Opportunities for therapeutic intervention

“…There is also growing evidence that gut-lung axis and gut microbiota induced inflammation may lead to the development of chronic inflammatory disorders of the respiratory as well as GI tract [111]. It has been demonstrated that autoimmunity of the lungs can be driven by Th17 cells that are induced by SFB in the gut by promoting inducible bronchus associated lymphoid tissues, a type of ectopic lymphoid tissues in the lung of rheumatoid arthritis patients [112]. Therefore, manipulating the gut microbiota may also be useful in the treatment of respiratory diseases.…”