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Clin Exp Immunol. 2020 Jan 6. doi: 10.1111/cei.13414. [Epub ahead of print]

Phenotypic shift of small intestinal intra-epithelial type 1 innate lymphoid cells in celiac disease is associated with enhanced cytotoxic potential.

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Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, New York, NY, USA.
Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, USA.
Department of Pathology, Department of Medicine, New York University Langone Medical Center, New York, NY, USA.
Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.


The small intestinal (SI) epithelium harbors a heterogeneous population of lymphocytes that mediate mucosal damage and repair in celiac disease (CD). The composition and roles of human proximal SI intra-epithelial innate lymphoid cells (ILCs), and their alterations in CD, are not well understood. We report that duodenal intra-epithelial ILCs predominantly consist of natural killer (NK)p44+ CD127- cytotoxic ILC1s and NKp44- CD127+ helper ILC1s, while ILC3s only represent a minor population. In patients with newly diagnosed or active CD (ACD) and refractory CD type 1 (RCD I), the frequency of SI NKp44+ ILCs is decreased, with restoration of NKp44+ ILC frequency observed in patients adhering to a gluten-free diet who show evidence of mucosal healing. Moreover, the frequency of SI NKp44- ILCs is increased in ACD and RCD I patients and correlates with the severity of villous atrophy and epithelial damage, as assessed by serum levels of fatty acid binding protein 2 (FABP2). We show that the ILC alterations in CD represent a phenotypic shift of cytotoxic ILC1s rather than an increase in helper ILC1s or transdifferentiation of ILC1s to ILC3s, and activation-induced loss of NKp44 by cytotoxic ILC1s is associated with increased interferon (IFN)-γ expression and release of lytic granules. These findings suggest that intra-epithelial NKp44- CD127- cytotoxic ILC1s may contribute to mucosal damage in CD.


autoimmunity; cell surface molecules; human; inflammation; innate lymphoid cells


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