Epithelial CD74 regulates intestinal barrier homeostasis
7 affiliations
- 1Regulation of Host Defense Team, Division of Microbiology and Immunology, Center for Infectious Disease Education and Research, Osaka University
- 2Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, University of Osaka
- 3World Premier International Research Center Initiative (WIP) Immunology Frontier Research Center, University of Osaka
- 4Institute for Advanced Co-Creation Studies, University of Osaka
- 5Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University
- 6Center for Infectious Disease Education and Research, University of Osaka
- 7Center for Advanced Modalities and Drug Delivery System (DDS), Osaka University
Abstract
CD74, originally identified as the invariant chain of MHC class II, also functions as a receptor for macrophage migration inhibitory factor (MIF). Although CD74 is expressed in various non-lymphoid cells, including epithelial cells across multiple organs, the regulation and functional significance of its expression in these tissues remain poorly understood. Here, we show that CD74 is constitutively expressed in small intestinal epithelial cells, particularly within stem and transit-amplifying compartments, and that its expression is influenced by microbiota and IFN-γ signaling. Conditional deletion of CD74 in IECs (CD74 ΔIEC mice) resulted in increased intestinal permeability under steady-state conditions, which was consistent with reduced expression of the tight junction protein ZO-1. While the numbers of intestinal stem cells and Paneth cells remained unchanged, CD74-deficient mice also exhibited elongation of the small intestine and enhanced crypt cell proliferation. Single-cell RNA sequencing revealed enrichment of mitochondrial pathways in CD74-deficient IECs. Consistent with these findings, CD74-deficient IECs exhibited increased mitochondrial content and altered mitochondrial membrane potential. Organoid cultures further showed accelerated growth and increased proliferation in the absence of CD74. Together, these findings suggest that CD74 contributes to intestinal epithelial homeostasis by limiting epithelial proliferation and supporting tight junction integrity, thereby helping to maintain barrier function under steady-state conditions.
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BibTeX
@article{kohyama2026epithelial,
title = {{Epithelial CD74 regulates intestinal barrier homeostasis}},
author = {Masako Kohyama and Koichi Iwatani and Sakiko Tomita and Takayoshi Ito and Hisako Kayama and Daisuke Motooka and Hisashi Arase and Kiyoshi Takeda and Wataru Ise},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1856250},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1856250/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Epithelial CD74 regulates intestinal barrier homeostasis
AU - Masako Kohyama
AU - Koichi Iwatani
AU - Sakiko Tomita
AU - Takayoshi Ito
AU - Hisako Kayama
AU - Daisuke Motooka
AU - Hisashi Arase
AU - Kiyoshi Takeda
AU - Wataru Ise
PY - 2026
DA - 2026/10/30
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1856250
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1856250/full
AB - CD74, originally identified as the invariant chain of MHC class II, also functions as a receptor for macrophage migration inhibitory factor (MIF). Although CD74 is expressed in various non-lymphoid cells, including epithelial cells across multiple organs, the regulation and functional significance of its expression in these tissues remain poorly understood. Here, we show that CD74 is constitutively expressed in small intestinal epithelial cells, particularly within stem and transit-amplifying compartments, and that its expression is influenced by microbiota and IFN-γ signaling. Conditional deletion of CD74 in IECs (CD74 ΔIEC mice) resulted in increased intestinal permeability under steady-state conditions, which was consistent with reduced expression of the tight junction protein ZO-1. While the numbers of intestinal stem cells and Paneth cells remained unchanged, CD74-deficient mice also exhibited elongation of the small intestine and enhanced crypt cell proliferation. Single-cell RNA sequencing revealed enrichment of mitochondrial pathways in CD74-deficient IECs. Consistent with these findings, CD74-deficient IECs exhibited increased mitochondrial content and altered mitochondrial membrane potential. Organoid cultures further showed accelerated growth and increased proliferation in the absence of CD74. Together, these findings suggest that CD74 contributes to intestinal epithelial homeostasis by limiting epithelial proliferation and supporting tight junction integrity, thereby helping to maintain barrier function under steady-state conditions.
SN - 1664-3224
ER -