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). TCR gamma delta+ IELs play an important role in mucosal repair, homeostasis, and tumor surveillance. Recently, human small intestinal TCR gamma delta+ IELs were shown to have regulatory potential in uncomplicated celiac disease (CD). AIM: In the present study, we investigated whether TCR gamma delta+ 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 Multiparameter flow cytometric immunophenotyping was performed on IELs isolated from fresh AND METHODS: small bowel biopsy specimens of relatively large distinct CD patient and control groups (N = 87). RESULTS: A significantly lower percentage of TCR gamma delta+ IELs was found in RCD II as compared to all other CD groups. In contrast, in uncomplicated CD patients significantly more TCR gamma delta+ IELs were found than in controls. Overall, there is a clear negative relation between TCR gamma delta+ IELs and aberrant IELs. Interestingly, TCR gamma delta+ IELs increase again in RCD II after effective therapy. CONCLUSIONS: The observed negative relation between TCR gamma delta+ and aberrant IELs, along with their known regulatory capacity in uncomplicated CD, implies that TCR gamma delta+ 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. (Am J Gastroenterol 2008;103:3152-3158).