Reprogramming of CTLs into natural killer-like cells in celiac disease.
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.
Meresse
Bertrand
B
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Curran
Shane A
SA
Ciszewski
Cezary
C
Orbelyan
Gerasim
G
Setty
Mala
M
Bhagat
Govind
G
Lee
Leanne
L
Tretiakova
Maria
M
Semrad
Carol
C
Kistner
Emily
E
Winchester
Robert J
RJ
Braud
Veronique
V
Lanier
Lewis L
LL
Geraghty
Daniel E
DE
Green
Peter H
PH
Guandalini
Stefano
S
Jabri
Bana
B