Gluten-Dependent Activation of CD4+ T Cells by MHC Class II-Expressing Epithelium

doi:10.1053/j.gastro.2024.07.008

Gluten-Dependent Activation of CD4+ T Cells by MHC Class II-Expressing Epithelium

2024-11-01

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María Inés Pinto-Sánchez

DOI：10.1053/j.gastro.2024.07.008

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BACKGROUND & AIMS: Intestinal epithelial cell (IEC) damage is a hallmark of celiac disease (CeD); however, its role in gluten-dependent T-cell activation is unknown. We investigated IEC-gluten-T-cell interactions in organoid monolayers expressing human major histocompatibility complex class II (HLA-DQ2.5), which facilitates gluten antigen recognition by CD4 & thorn; T cells in CeD. METHODS: Epithelial major histocompatibility complex class II (MHCII) was determined in active and treated CeD, and in nonimmunized and gluten- immunized DR3-DQ2.5 transgenic mice, lacking mouse MHCII molecules. Organoid monolayers from DR3-DQ2.5 mice were treated with or without interferon (IFN)-g, and MHCII expression was evaluated by fl ow cytometry. Organoid monolayers and CD4 & thorn; T-cell co-cultures were incubated with gluten, predigested, or not by elastase-producing Pseudomonas aeruginosa or its lasB mutant. T-cell function was assessed based on proliferation, expression of activation markers, and cytokine release in the co-culture supernatants. RESULTS: Patients with active CeD and gluten-immunized DR3-DQ2.5 mice demonstrated epithelial MHCII expression. Organoid monolayers derived from gluten-immunized DR3DQ2.5 mice expressed MHCII, which was upregulated by IFN-g. In organoid monolayer T-cell co-cultures, gluten increased the proliferation of CD4 & thorn; T cells, expression of Tcell activation markers, and the release of interleukin-2, IFNg, and interleukin-15 in co-culture supernatants. Gluten metabolized by P aeruginosa, but not the lasB mutant, enhanced CD4 & thorn; T-cell proliferation and activation. CONCLUSIONS: Gluten antigens are efficiently presented by MHCII-expressing IECs, resulting in the activation of gluten- specific CD4 & thorn; T cells, which is enhanced by gluten predigestion with microbial elastase. Therapeutics directed at IECs may offer a novel approach for modulating both adaptive and innate immunity in patients with CeD.

Keywords:

Celiac Disease

Organoid Monolayers

MHC Class II

T-Cell Activation

Gluten

Microbial Metabolism

Gluten-Dependent Activation of CD4+ T Cells by MHC Class II-Expressing Epithelium

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