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The Presence of Small Intestinal Intraepithelial Gamma/Delta T-Lymphocytes Is Inversely Correlated With Lymphoma Development in Refractory Celiac Disease

BACKGROUND:In refractory celiac disease (RCD) type II, a phenotypically aberrant (CD7+ CD3− CD4/8-cytoplasmicCD3+) intraepithelial lymphocyte (IEL) population is present, and 50–60% of these patients develop enteropathy-associated T-cell lymphoma (EATL). TCRγδ+ IELs play an important role in mucosal repair, homeostasis, and tumor surveillance. Recently, human small intestinal TCRγδ+ IELs were shown to have regulatory potential in uncomplicated celiac disease (CD).AIM:In the present study, we investigated whether TCRγδ+ IELs are decreased in RCD II, providing a possible explanation for persisting mucosal damage and inflammation, and the emergence of aberrant T cells with clonal expansion to EATL.DESIGN AND METHODS:Multiparameter flow cytometric immunophenotyping was performed on IELs isolated from fresh small bowel biopsy specimens of relatively large distinct CD patient and control groups (N = 87).RESULTS:A significantly lower percentage of TCRγδ+ IELs was found in RCD II as compared to all other CD groups. In contrast, in uncomplicated CD patients significantly more TCRγδ+ IELs were found than in controls. Overall, there is a clear negative relation between TCRγδ+ IELs and aberrant IELs. Interestingly, TCRγδ+ IELs increase again in RCD II after effective therapy.CONCLUSIONS:The observed negative relation between TCRγδ+ and aberrant IELs, along with their known regulatory capacity in uncomplicated CD, implies that TCRγδ+ IELs may play a crucial role in mucosal repair, regaining homeostasis and possibly even tumor surveillance. These cells may be important markers, in addition to the aberrant T cells, to differentiate between disease categories and to evaluate the effectiveness of therapeutic strategies.