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

Clin Exp Immunol. 2020 May;200(2):163-175. doi: 10.1111/cei.13414. Epub 2020 Jan 27.


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.

Keywords: autoimmunity; cell surface molecules; human; inflammation; innate lymphoid cells.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Celiac Disease* / immunology
  • Celiac Disease* / pathology
  • Cell Transdifferentiation / immunology*
  • Child
  • Child, Preschool
  • Duodenum* / immunology
  • Duodenum* / pathology
  • Female
  • Humans
  • Immunity, Innate
  • Infant
  • Intestinal Mucosa* / immunology
  • Intestinal Mucosa* / pathology
  • Lymphocytes* / immunology
  • Lymphocytes* / pathology
  • Male