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¹ Department of Pathology, ² Department of Pediatrics, ³ Department of Medicine, and ⁴ Department of Health Studies, University of Chicago, Chicago, IL 60637
⁵ Division of Autoimmune and Molecular Diseases, ⁶ Department of Pathology, and ⁷ Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032
⁸ Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique/Université de Nice-Sophia Antipolis, UMR6097, 06560 Valbonne, France
⁹ Department of Microbiology and Immunology, and the Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143
¹⁰ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

CORRESPONDENCE Bana Jabri: bjabri{at}bsd.uchicago.edu

Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon –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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