Reprogramming of CTLs into natural killer–like cells in celiac disease
Open accessAbstract
Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon γ–producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.
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Under stress or inflammatory conditions, such as in celiac disease, iIELs upregulate the expression of activating NKG2D and CD94/NKG2C receptors (which recognize MICA/B and HLA-E, respectively) while losing the expression of the inhibitory receptors CD94/NKG2A.
“Under stress or inflammatory conditions, such as in celiac disease, iIELs upregulate the expression of activating NKG2D and CD94/NKG2C receptors, (which recognize MICA/B and HLA-E, respectively) while losing the expression of the inhibitory receptors CD94/NKG2A [302, 306-308].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [306]
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- Authors
- Meresse, B., Curran, S. A., Ciszewski, C., Orbelyan, G., Setty, M., Bhagat, G., Lee, L., Tretiakova, M., Semrad, C., Kistner, E., Winchester, R. J., Braud, V., Lanier, L. L., Geraghty, D. E., Green, P. H., Guandalini, S., & Jabri, B.
- Affiliations
- 1Department of Pathology,
- 2Department of Pediatrics,
- 6Department of Pathology, and
- 3Department of Medicine, and
- University of Chicago (US)
- 5Division of Autoimmune and Molecular Diseases,
- 8Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique/Université de Nice-Sophia Antipolis, UMR6097, 06560 Valbonne, France
- University of California, San Francisco (US)
- Fred Hutch Cancer Center (US)
- Columbia University (US)
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2006-05-08
- Volume
- 203
- Issue
- 5
- Pages
- 1343-1355
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2121214
- OpenAlex
- W2128452798
- Cited by
- 322
- References
- 68
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 22 · 2023: 13 · 2022: 10 · 2021: 27 · 2020: 16 · 2019: 13 · 2018: 12 · 2017: 12 · 2016: 13 · 2015: 14 · 2014: 15 · 2013: 16 · 2012: 16
- FWCI
- 21.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01 CA89294, R01CA089294)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058727, R01DK58727, R01DK063158)
- Topics
- Health Sciences › Medicine › Gastroenterology › Celiac Disease Research and Management
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- celiac disease, cytotoxic T lymphocytes, NKG2C, NKp44, NKp46, ZAP-70, interferon-gamma, intraepithelial lymphocytes, cytomegalovirus, lymphoma, intestinal epithelial damage, chronic inflammation, immunopathology
- MeSH terms
- Base Sequence, Celiac Disease, Cell Differentiation, Chronic Disease, Cytomegalovirus Infections, Gene Expression Regulation, Humans, Interferon-gamma, Intestinal Mucosa, Intestine, Small, Killer Cells, Natural, Lymphoma, Molecular Sequence Data, Phosphorylation, Protein Processing, Post-Translational, Receptors, Immunologic, T-Lymphocytes, Cytotoxic, Signal Transduction, Gene Expression Profiling, Cell Proliferation, ZAP-70 Protein-Tyrosine Kinase
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