Dynamics of Non-conventional Intraepithelial Lymphocytes-NK, NKT, and γδ T-in Celiac Disease: Relationship with Age, Diet, and Histopathology

Intraepithelial lymphocytes (IEL) are a heterogeneous population of lymphocytes raised in celiac disease (CD), whose role in CD pathogenesis remains to be defined. To investigate how the age of diagnosis, diet, and the severity of the histological lesions are related to the changes observed in unconventional IEL populations. Prospective analysis of 101 confirmed celiac patients from a single center, including 66 at diagnosis (45 children, 21 adults) and 112 non-celiac controls (12 children, 100 adults). IEL from duodenal biopsies were studied by six-color flow cytometry. The results were analyzed in relationship with age, diet (gluten intake), and histopathology (Marsh type). In comparison with respective age controls, both children and adult patients showed duodenal intraepithelial lymphocytosis with significant differences in every single non-conventional IEL population: CD3+ TCR gamma delta, NK (CD3-, CD16+, CD56+), NKT (CD3+, CD161+, CD56+), and iNKT (CD3+ V alpha 24) (P < 0.001 for all). Gluten intake was not only directly associated with severe atrophy, but also with decreased percentages of NK (P = 0.02), NKT (P = 0.003), and iNKT (P = 0.03). Changes in iNKT and gamma delta IEL were more marked in celiac children compared with celiac adults (P = 0.02 and 0.01, respectively). In contrast, increased CD3+ TCR gamma delta were diet- and Marsh grade-independent. The typical phenotypical profile of intraepithelial lymphocytosis in untreated pediatric and adult celiacs consists of increased CD3+ TCR gamma delta populations with decreased NK, NKT, and iNKT cells. NK, NKT, and iNKT IEL, but not gamma delta IEL, are dynamic populations associated with diet, age, and histopathology.