T-cell receptor (TCR) signaling abnormalities and gut dysbiosis are thought to be involved in the development of systemic lupus erythematosus (SLE). However, it is not known whether these mechanisms are interrelated. This study explored the impact of defective TCR signaling on microbiota-driven immune responses and the consequent triggering of systemic autoimmunity.
The responses of B6SKG mice harboring a mutation in the zeta-chain-associated protein kinase 70 in terms of spontaneous development of SLE were evaluated in specific-pathogen- and germ-free conditions. Gut microbiome was analyzed using 16S rRNA sequencing. Secretory immunoglobulin (Ig)A production in the gut and T follicular helper cells (Tfh) development in the spleen and Peyer's patches were analyzed. Interleukin (IL)-17-deficient mice and segmented filamentous bacteria (SFB)-specific TCR transgenic mice were used to examine the role of IL-17 and thymic selection.
SLE development by B6SKG mice was significantly more attenuated in germ free conditions than in specific -pathogen-free conditions. The gut microbiota in B6SKG mice was altered, which was associated with the expansion of SFB and consequent development of SLE by driving Thelper 17 (Th17)-cell differentiation, which was in turn blunted by IL-17 deficiency. Notably, although systemic Tfh development and autoantibody IgG response were enhanced, local gut Tfh and IgA responses were impaired. Moreover, experiments in SFB-specific TCR transgenic mice revealed that this differential response was caused by altered thymic selection of self- and microbiota-reactive TCR because of defective TCR signaling.
Defective TCR signaling alters the gut microbiota and promotes systemic autoimmunity by driving Th17-cell differentiation.