CellJun 16, 2023

Gasdermin D may help trigger MHCII production to support food tolerance in the small intestine.

Updated Dec 18, 2025

Abstract

IEC accumulation of a 13-kD GSDMD fragment may help balance immunity and food tolerance.

Intestinal epithelial cells (IECs) act as a barrier to foreign antigens.
A 13-kD fragment of GSDMD is produced by caspase-3/7 when exposed to dietary antigens.
This fragment moves to the nucleus and promotes the production of CIITA and MHCII molecules.
CIITA and MHCII are linked to the development of Tr1 cells in the upper small intestine.
Mice lacking certain components showed disrupted food tolerance, suggesting a key regulatory role for GSDMD cleavage.

Simplified

The intestinal epithelial cells (IECs) constitute the primary barrier between host cells and numerous foreign antigens; it is unclear how IECs induce the protective immunity against pathogens while maintaining the immune tolerance to food. Here, we found IECs accumulate a less recognized 13-kD N-terminal fragment of GSDMD that is cleaved by caspase-3/7 in response to dietary antigens. Unlike the 30-kD GSDMD cleavage fragment that executes pyroptosis, the IEC-accumulated GSDMD cleavage fragment translocates to the nucleus and induces the transcription of CIITA and MHCII molecules, which in turn induces the Tr1 cells in upper small intestine. Mice treated with a caspase-3/7 inhibitor, mice with GSDMD mutation resistant to caspase-3/7 cleavage, mice with MHCII deficiency in IECs, and mice with Tr1 deficiency all displayed a disrupted food tolerance phenotype. Our study supports that differential cleavage of GSDMD can be understood as a regulatory hub controlling immunity versus tolerance in the small intestine.

Full Text

Full text is available at the source.

View Full Text ↗

Funding

Competing interests

Declaration of interests S.Z. is a cofounder of Ibiome which studies microbial regulation of immune responses. R.A.F. is a cofounder of Ventus, which studies inflammatory pathways. Both in topics unrelated to the subject of this work.

PubMed

Abstract

Full Text

Funding

Competing interests

What Lands in Your Inbox Each Week: