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CD4+ Foxp3+ regulatory T cells (Treg) are essential to maintain immune tolerance, as their loss leads to a fatal autoimmune syndrome in mice and humans. Conflicting findings have been reported concerning their metabolism. Some reports found that Treg have low mechanistic target of rapamycin (mTOR) activity and would be less dependent on this kinase compared with conventional T cells, whereas other reports suggest quite the opposite. In this study, we revisited this question by using mice that have a specific deletion of mTOR in Treg. These mice spontaneously develop a severe and systemic inflammation. We show that mTOR expression by Treg is critical for their differentiation into effector Treg and their migration into nonlymphoid tissues. We also reveal that mTOR-deficient Treg have reduced stability. This loss of Foxp3 expression is associated with partial Foxp3 DNA remethylation, which may be due to an increased activity of the glutaminolysis pathway. Thus, our work shows that mTOR is crucial for Treg differentiation, migration, and identity and that drugs targeting this metabolism pathway will impact on their biology.

Summary Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using Toll-like receptor 7 (TLR7)-dependent mouse models of systemic lupus erythematosus (SLE), we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated by dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of L. reuteri in mice and fecal enrichment of Lactobacillus in a subset of SLE patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement, and mortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that promotes interferon pathways implicated in the pathogenesis of human autoimmunity.

Diet-induced modulation of host immune-microbiota interactions could be an attractive way to ameliorate autoimmunity. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with no cure. We used resistant starch (RS) as a novel approach to prevent SLE. We fed RS to a spontaneous TLR7 Tg and TLR7 agonist (Imiquimod, IMQ)-inducible lupus model to modulate gut microbial communities and lupus pathogenesis. Depletion of the gut microbiota with antibiotics reduced mortality in TLR7 Tg mice. Also, IMQ-induced lupus was ameliorated in GF compared to SPF B6 mice, supporting a role for the microbiota in the pathogenesis. In both models, RS reduced mortality, kidney involvement, hepatosplenomegaly, and type I interferons. Plasmacytoid dendritic cell (pDC) accumulation and type I interferon signaling in spleen and Peyer’s patches was also reduced. Fecal 16S rDNA sequencing and culture of internal organs revealed that Lactobacillus reuteri translocates to MLN, liver and spleen in TLR7 Tg mice, and that fecal loads and translocation were suppressed by RS. Lupus induction by IMQ in GF B6 mice was exacerbated by L. reuteri monocolonization. In addition, L. reuteri gavage in the IMQ-inducible model worsened lupus manifestations, which were prevented by RS feeding before onset of disease. RS induced short-chain fatty acids (SCFA) in ileum and blood of TLR7 Tg mice, which suppressed growth of L. reuteri in vitro. In summary, RS exerts beneficial effects in lupus-prone hosts through suppression of pathobionts and type I interferon pathways, which are known to contribute to human SLE. This study provides novel insights into diet-host-microbiota interactions and may aid in the development of functional foods to treat autoimmune diseases.