Intestinal intraepithelial lymphocytes (i-IEL) are phenotypically diverse and consist of both thymically derived and extrathymically derived cells. Extrathymically derived i-IEL are clearly different from thymically derived peripheral T cells in their phenotype and repertoire selection. The major locus of differentiation of extrathymically derived i-IEL appears to be the intestinal epithelium because recombination activating gene (RAG)-1 is expressed in CD3⁻ i-IEL. Extrathymic differentiation however does not imply independence from the thymus as athymic mice have increased numbers of CD3⁻CD8⁻ and CD3⁻CD8αα⁺ i-IEL but decreased numbers of CD3⁺CD8αα⁺ i-IEL when compared to euthymic mice. We speculate from these results that thymus-derived cytokine(s)/factor(s) may support differentiation from CD3⁻CD8αα⁺ to CD3⁺CD8αα⁺ i-IEL in the intestinal epithelium.

I-IEL seem to have some role in immune surveillance because they reside at a site which may represent a first line of defense against pathogenic organisms. This idea is supported by the reports showing in vivo activation of i-IEL under conditions of intestinal infection or tumor-bearing state. In vitro analyses showed cytotoxicity and cytokine production of i-IEL but their true function(s) in vivo is(are) not well known. Clearly more analysis on the in vivo function(s) of i-IEL are needed in order to clarify the true role(s) of i-IEL.