Skip to main content
eScholarship
Open Access Publications from the University of California

Reprogramming of CTLs into natural killer-like cells in celiac disease

  • Author(s): Meresse, Bertrand
  • Curran, Shane A
  • Ciszewski, Cezary
  • Orbelyan, Gerasim
  • Setty, Mala
  • Bhagat, Govind
  • Lee, Leanne
  • Tretiakova, Maria
  • Semrad, Carol
  • Kistner, Emily
  • Winchester, Robert J
  • Braud, Veronique
  • Lanier, Lewis L
  • Geraghty, Daniel E
  • Green, Peter H
  • Guandalini, Stefano
  • Jabri, Bana
  • et al.
Abstract

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

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content
Current View