Concomitant increase of IL-10 and pro-inflammatory cytokines in intraepithelial lymphocyte subsets in celiac disease

Celiac disease (CD) is a small intestinal enteropathy caused by permanent intolerance to wheat gluten. Active disease is characterized by a prominent cytokine response of intraepithelial lymphocytes (IELs) to gluten-containing diet with concomitant increase in expression of proinflammatory IFN-gamma and down-regulatory IL-10 without increase in tumor necrosis factor-alpha (TNF-alpha) or transforming growth factor-beta 1 (TGF-beta 1). The aim was to understand the local immune reaction by determining which intraepithelial T cell subsets produce the different cytokines. The three major IEL-subsets gamma delta IELs, CD4(+) abIELs and CD8(+) alpha beta IELs, as well as CD94(+) CD8(+) alpha beta IELs, selectively expanded in active CD, were retrieved from small intestinal biopsies of children with active CD and controls and analyzed quantitatively for cytokine mRNA expression. In active CD, CD8(+) alpha beta IELs showed a significant increase in expression levels of both IFN-gamma and IL-10. CD8(+) alpha beta IELs were also the IEL subset with highest expression level per cell of both cytokines and constituted the cellular source for almost all IFN-g and most IL-10. Expression levels of both cytokines were higher in CD94-CD8(+) alpha beta IELs than CD94(+) CD8(+) alpha beta IELs. TNF-alpha levels were only increased in CD4(+) alpha beta IELs, which also showed the highest expression level per cell and constituted the major source of this cytokine. Interestingly, IL-10 was increased also in CD4(+) alpha beta IELs. Cytokine levels were low in gamma delta IELs. 'Classical' CD94-CD8(+) alpha beta T cells within the epithelium are responsible for the excessive production of IFN-gamma, believed to drive the formation of intestinal lesions in active CD. Production of IL-10 may be a common feature of IELs producing pro-inflammatory cytokines, thereby attempting to limit inflammation in an autocrine fashion.