Summary: For years researchers have suspected that the gut influences multiple sclerosis (MS), but a clear cellular link remained missing. A new landmark study identifies intestinal epithelial cells (IECs) — the cells that line the gut — as unintended immune messengers that can trigger pathogenic responses contributing to MS.
The researchers discovered that in MS, IECs abnormally express MHC class II (MHC II) molecules, allowing them to present antigens to CD4+ T cells. This aberrant presentation promotes development of inflammatory Th17 cells in the gut, which then migrate from the intestine to the central nervous system (CNS), where they contribute to neuroinflammation and damage to the brain and spinal cord.
Key Facts
- Accidental antigen presenters: Intestinal epithelial cells normally act as a barrier and interact with microbes, but they rarely present antigens via MHC II. In MS and a mouse model of the disease, IECs upregulate MHC II and prime CD4+ T cells toward a pathogenic phenotype.
- Th17 trafficking: Using Kaede photoconversion to label gut immune cells, investigators tracked gut-primed Th17 cells as they migrated to the spinal cord, directly linking gut activation to CNS inflammation.
- Human validation: Single-cell RNA sequencing of intestinal biopsies from MS patients revealed inflammatory signatures and increased Th17 cells consistent with mouse findings, supporting a conserved gut–CNS axis in humans.
- Therapeutic implications: Current MS therapies often target circulating B cells. This work suggests new strategies focused on the gut — for example, modifying the intestinal environment or blocking epithelial antigen presentation to prevent generation of encephalitogenic T cells.
Source: Keio University
Multiple sclerosis (MS) is a chronic neurological disorder driven by misdirected immune responses against the central nervous system (CNS).
How does the body begin attacking its own nervous system?
Autoimmune damage in MS arises when immune cells fail to distinguish self from non-self and attack myelin, the insulating layer around neurons. Genetics, environmental exposures and the gut microbiome all influence MS risk and progression, but the exact cellular pathways connecting the gut and the brain have been unclear.
Patients with MS commonly show altered gut microbiota and changes in microbial metabolites that can shape systemic immune responses. Yet defining which cells translate gut-derived signals into pathogenic immune activity in the CNS has been a major gap in understanding.
Published online March 27, 2026, in Science Immunology, the new study reveals how gut immune responses can initiate neuroinflammation. The work was led by Dr. Shohei Suzuki and Dr. Tomohisa Sujino at Keio University, who aimed to clarify how intestinal immunity and microbial cues contribute to CNS autoimmune disease.
Following earlier observations of mild ileal inflammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, the team analyzed intestinal biopsies from MS patients with single-cell RNA sequencing. They found increased Th17 cells and upregulation of antigen presentation pathways in IECs in both mice and humans, indicating a conserved mechanism across species.
IECs from the ileum showed particularly high MHC II expression during EAE. When the authors selectively removed MHC II from IECs in mice, generation of pathogenic Th17 cells decreased and disease severity was reduced, demonstrating a causal role for epithelial antigen presentation in disease initiation.
Although IECs are not classical antigen-presenting cells, coculture experiments with IECs and CD4+ T cells showed that IECs can present antigen in an MHC II–dependent way and induce Th17 polarization. These gut-primed Th17 cells displayed pro-inflammatory characteristics linked to CNS autoimmunity.
To show that gut-induced Th17 cells migrate to the CNS, researchers used Kaede transgenic mice. Photoconversion temporarily changed the color of immune cells in the gut, allowing the team to trace those cells as they trafficked to the spinal cord and promoted neuroinflammation.
Together, the findings position epithelial MHC II expression as a pivotal step in expanding encephalitogenic Th17 cells that later travel to the CNS. This work provides a direct mechanistic bridge between the gut mucosa and autoimmune neuroinflammation.
The study highlights the gut mucosal compartment as a formative environment for effector T cell programming that can influence distant tissues like the brain — a concept with important therapeutic implications.
“Most MS treatments focus on blood-based immune cells such as B cells,” said the authors. “Targeting the gut environment or blocking antigen presentation by IECs may offer new, localized strategies to prevent or limit CNS autoimmunity without broad systemic immunosuppression.”
A clearer understanding of gut mucosal immunity and epithelial–immune interactions may therefore guide development of targeted therapies for MS and related neuroinflammatory disorders.
Funding information
This research was funded by the Japan Science and Technology Agency (JST) FOREST program (grant 21457195); Grants-in-Aid from the Japan Society for the Promotion of Science (JSPS) (grants 20H00536, 20H03665, 21K18272, 23H02899, 23K27590, 25K22627); the Japan Agency for Medical Research and Development (CREST grant 21gm1510002h0001); KGRI Challenge grant; Sakaguchi Memorial Foundation; and Miyarisan Pharmaceuticals.
Key Questions Answered:
A: The gut can serve as a training site for immune cells. This study shows that the gut lining can present antigens in a way that misdirects CD4+ T cells into becoming inflammatory Th17 cells, which can then leave the intestine and home to the spinal cord and brain to cause damage.
A: The findings emphasize immune activity in the gut more than diet alone. While diet influences the microbiome and gut environment, therapies that directly modulate intestinal immunity or epithelial antigen presentation — so-called luminal therapies — may be a more targeted way to correct harmful immune training without broad immune suppression.
A: They used Kaede photoconversion to mark immune cells in the gut with a color change and later detected those same marked cells in the spinal cord, directly demonstrating migration of gut-primed Th17 cells to the CNS.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full.
- Additional context was provided by our editorial staff.
About this multiple sclerosis research news
Author: Tetyana Khatayeva
Source: Keio University
Contact: Tetyana Khatayeva – Keio University
Image: Image credit: Neuroscience News
Original Research: Closed access.
“Intestinal epithelial MHC class II induces encephalitogenic CD4⁺ T cells and initiates central nervous system autoimmunity” by Raffaele Palladino, Alan Thompson, and Olga Ciccarelli. Science Immunology
DOI: 10.1126/sciimmunol.aec1627
Abstract
Intestinal epithelial MHC class II induces encephalitogenic CD4⁺ T cells and initiates central nervous system autoimmunity
The intestinal epithelium mediates critical interactions between the immune system and the microbiota, but its role in systemic autoimmunity has not been fully defined.
This study identifies intestinal epithelial cells (IECs) as initiators of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. In both EAE mice and patients with MS, IECs upregulate antigen presentation pathways and correlate with increased intestinal T helper 17 (Th17) cell accumulation.
Epithelial MHC II expression was notably elevated during EAE, especially in the ileum, and conditional deletion of MHC II from IECs diminished pathogenic Th17 generation and reduced disease severity.
Using parabiosis and photoconversion models, the authors show that Th17 cells induced in the intestinal lamina propria migrate to the spinal cord. Coculture experiments further demonstrate that IEC organoids presenting myelin antigen drive RORγt+ CD4+ T cell differentiation in an MHC II–dependent manner.
These results reveal a conserved gut–CNS axis in autoimmunity and identify epithelial antigen presentation as a key initiator of neuroinflammation.