Published papers

Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.

The bone tissue serves as a dynamic reservoir that accommodates diverse immune cell populations during low-energy states such as fasting. Energy restriction and reduced metabolism induce a transient migration of naïve B cells from Peyer’s patches to the bone marrow in mice, a process driven by the upregulation of Cxcl13 expression within the bone niche. However, the specific cellular source of CXCL13 and the upstream signals regulating its expression remain undefined. Our analysis identified the lineage-negative fraction of the bone as the major source of CXCL13. Single-cell RNA sequencing of these cells further demonstrated that Cxcl13 was selectively expressed by osteogenic mesenchymal stromal cells (MSCs) during fasting. Consistently, immunofluorescence imaging showed an increased frequency of these CXCL13-producing cells under fasting conditions, primarily localized within the perivascular niche. Gene Ontology analysis of differentially expressed genes in these cells during fasting revealed enrichment of TGF-β and PPAR signaling. In line with this, pharmacological intervention in either the TGF-β or PPARγ signaling pathway significantly attenuated fasting-induced naïve B-cell migration and CXCL13 production in the bone. These results establish a mechanistic link between systemic metabolic cues and the bone marrow immune microenvironment. We propose that osteogenic MSCs play a vital role in orchestrating this trafficking program for naïve B cells, underscoring a dynamic crosstalk between the bone stromal cells and the immune system.

The commensal microbiota plays a crucial role in shaping mucosal immunity, particularly in the induction of T follicular helper (Tfh) cells and subsequent B cell IgA production. Here, we demonstrate that dietary soy elicits a robust Tfh cell and IgA response in Peyer’s patches of weaning mice. Soy feeding promotes the expansion of two principal commensal bacterial species, Limosilactobacillus reuteri and Muribaculum intestinale. Mechanistically, L. reuteri provides cognate antigens for Tfh cell activation, while M. intestinale functions as an adjuvant by promoting IL-1β production from myeloid cells. The resulting IgA exhibits polyreactivity and enhances protection against Salmonella infection. These findings highlight the specific interplay among dietary components, intestinal microbiota, and mucosal immunity, thereby establishing a diet-microbe-immune axis that shapes host defense in early life. This axis represents a promising therapeutic target for developing future strategies to enhance resistance to enteric pathogens.

Interleukin-17-producing γδT cells (γδT17 cells) play a dual role in immune regulation, serving as both protectors in various tissues and orchestrators of inflammatory responses in autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis. However, the ontology and repertoires of encephalitogenic γδT17 cells remain unclear. In this study, we demonstrate that the encephalitogenicity of γδT17 cells is conferred through microfold cell (M cell)-dependent uptake of commensal bacteria in Peyer’s patches. Specifically, CXCR6hiVγ6+Vδ1+ invariant γδT17 cells are activated by specific commensal bacteria such as Lactobacillus spp., which stimulate TCR of CXCR6hiVγ6+Vδ1+ invariant γδT17 cells. During the early stages of EAE, γδT17 cells infiltrate the central nervous system (CNS), initiating a type 17 inflammatory response. Our findings illustrate that Peyer’s patch M cells serve as a critical bridge, linking the pathological association between commensal bacteria and the onset of CNS inflammation.

Anti-NMDA receptor (NMDAR) encephalitis is a devastating disease with severe psychiatric and neurological symptoms believed to be caused by pathogenic autoantibodies that bind to the N-terminal domain (NTD) of the NMDAR GluN1 subunit (GluN1-NTD) crosslinking adjacent NMDARs and driving their internalization. Here we describe ART5803, a humanized monovalent antibody, as a potential therapy for anti-NMDAR encephalitis. ART5803 binds with a high affinity (KD = 0.69 nM) to GluN1-NTD without affecting NMDAR activity or inducing internalization. ART5803 blocks NMDAR internalization induced by patients’ pathogenic autoantibodies, and restores NMDAR function. A marmoset animal model was developed using sustained intracerebroventricular (ICV) administration of a human pathogenic autoantibody to evoke behavioral and motor abnormalities. ART5803 ICV infusion or peripheral injections rapidly reversed these abnormalities. These data, together with the pharmacokinetic profile in cynomolgus monkeys, indicate a therapeutic potential for intravenous (IV)-administered ART5803 as a fast-acting and efficacious option for anti-NMDAR encephalitis.