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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.

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.

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