Objective Refractory coeliac disease type II (RCDII) is a severe complication of coeliac disease (CD) characterised by aberrant intraepithelial lymphocytes (IELs) of unknown origin that display an atypical CD3⁻CD7⁺icCD3⁺ phenotype. In approximately 40% of patients with RCDII these lymphocytes develop into an invasive lymphoma. In the current study we aimed to identify the physiological counterpart of these cells.

Design RCDII cell lines were compared with T-cell receptor positive (TCR⁺) IEL (T-IEL) lines by microarray analysis, real-time quantitative PCR and flow cytometry. This information was used to identify cells with an RCDII-associated phenotype in duodenal biopsies from non-refractory individuals by multicolour flow cytometry.

Results RCDII lines were transcriptionally distinct from T-IEL lines and expressed higher levels of multiple natural killer (NK) cell receptors. In addition to the CD3⁻CD7⁺icCD3⁺ phenotype, the RCDII lines were distinguishable from other lymphocyte subsets by the absence of CD56, CD127 and CD34. Cells matching this surface lineage-negative (Lin⁻) CD7⁺CD127⁻CD34⁻ phenotype expressed a functional interleukin-15 (IL-15) receptor and constituted a significant proportion of IELs in duodenal specimens of patients without CD, particularly children, and were also found in the thymus. In patients without CD, the Lin⁻CD7⁺CD127⁻CD34⁻ subset was one of four subsets within the CD3⁻CD7⁺icCD3⁺ population that could be distinguished on the basis of differential expression of CD56 and/or CD127.

Conclusion Our studies indicate that the CD3⁻CD7⁺icCD3⁺ population is heterogeneous and reveal the existence of a Lin⁻ subset that is distinct from T, B, NK and lymphoid tissue inducer cells. We speculate that this IL-15 responsive population represents the physiological counterpart of aberrant cells expanded in RCDII and transformed in RCDII-associated lymphoma.