Gliadin-specific CD4 ⁺ T cells exhibit functional diversity independent of TCR usage or epitope specificity
7 affiliations
- 1Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
- 2Department of Host-Microbe Interactions, St Jude Children’s Research Hospital, Memphis, TN, USA.
- 3Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
- 4Janssen Research and Development, Spring House, PA, USA.
- 5Immunology Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
- 6Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
- 7Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
Abstract
Celiac disease (CeD) is driven by pathogenic CD4 + T cell responses, primarily targeting four HLA-DQ2.5–restricted immunodominant epitopes derived from α-gliadin and ω-gliadin. While gliadin-specific CD4 + T cells have been investigated, how transcriptional and effector phenotypes in CeD vary across distinct epitope specificities remains unclear, as do the signature TCR motifs governing gliadin epitope specificity and cross-reactivity. Single-cell transcriptomic and TCR profiling of gliadin epitope-specific peripheral blood CD4 + T cells from patients with CeD after gluten challenge revealed T cells with an activated T H 1 effector, conventional regulatory T cell (T reg cell) or cytotoxic phenotypes across specificities, with no evidence of functional specialization driven by specific epitopes. Moreover, we identified core TCR motifs that dictate gliadin epitope specificity and cross-reactivity and elucidated the structural basis of their cognate pMHC recognition. These motifs enabled accurate prediction of gliadin specificity from unassigned TCRs. Collectively, these findings advance our understanding of immune responses in CeD and provide a foundation for tracking disease-relevant T cells.
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BibTeX
@article{jones2026gliadinspecific,
title = {{Gliadin-specific CD4 ⁺ T cells exhibit functional diversity independent of TCR usage or epitope specificity}},
author = {Claerwen M. Jones and Jia Jia Lim and Stefan A. Schattgen and Tiing Jen Loh and Hien Thy Dao and Mai T. Tran and Angela Nguyen and Pirooz Zareie and Nathan J. Felix and Paul G. Thomas and Melinda Y. Hardy and Jason A. Tye-Din and Hugh H. Reid and Jamie Rossjohn and Nicole L. La Gruta},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aei3175},
url = {https://www.science.org/doi/10.1126/sciadv.aei3175},
note = {CC BY},
}
RIS
TY - JOUR
TI - Gliadin-specific CD4 ⁺ T cells exhibit functional diversity independent of TCR usage or epitope specificity
AU - Claerwen M. Jones
AU - Jia Jia Lim
AU - Stefan A. Schattgen
AU - Tiing Jen Loh
AU - Hien Thy Dao
AU - Mai T. Tran
AU - Angela Nguyen
AU - Pirooz Zareie
AU - Nathan J. Felix
AU - Paul G. Thomas
AU - Melinda Y. Hardy
AU - Jason A. Tye-Din
AU - Hugh H. Reid
AU - Jamie Rossjohn
AU - Nicole L. La Gruta
PY - 2026
DA - 2026/10/02
JO - Science Advances
DO - 10.1126/sciadv.aei3175
UR - https://www.science.org/doi/10.1126/sciadv.aei3175
AB - Celiac disease (CeD) is driven by pathogenic CD4 + T cell responses, primarily targeting four HLA-DQ2.5–restricted immunodominant epitopes derived from α-gliadin and ω-gliadin. While gliadin-specific CD4 + T cells have been investigated, how transcriptional and effector phenotypes in CeD vary across distinct epitope specificities remains unclear, as do the signature TCR motifs governing gliadin epitope specificity and cross-reactivity. Single-cell transcriptomic and TCR profiling of gliadin epitope-specific peripheral blood CD4 + T cells from patients with CeD after gluten challenge revealed T cells with an activated T H 1 effector, conventional regulatory T cell (T reg cell) or cytotoxic phenotypes across specificities, with no evidence of functional specialization driven by specific epitopes. Moreover, we identified core TCR motifs that dictate gliadin epitope specificity and cross-reactivity and elucidated the structural basis of their cognate pMHC recognition. These motifs enabled accurate prediction of gliadin specificity from unassigned TCRs. Collectively, these findings advance our understanding of immune responses in CeD and provide a foundation for tracking disease-relevant T cells.
SN - 2375-2548
ER -