Locally resident intraepithelial lymphocytes (IELs) are primarily T cells with potent cytolytic and immunoregulatory capacities, which they use to sustain epithelial integrity. Here, we consider that most IEL compartments comprise a variable mixture of two cell types: T cells primed to conventional antigen in the systemic compartment and T cells with ill-defined reactivities and origins, whose properties seem to place them mid-way between the adaptive and innate immune responses. We review the capacity of IELs to limit the dissemination of infectious pathogens and malignant cells and to control the infiltration of epithelial surfaces by systemic cells. An improved characterization of IELs would seem essential if we are to understand how immune responses and immunopathologies develop at body surfaces.

Intraepithelial lymphocytes (IELs) are abundant, evolutionarily conserved T cells, commonly enriched in T cell receptor (TCR) gammadelta expression. However, their primary functional potential and constitutive activation state are incompletely understood. To address this, serial analysis of gene expression (SAGE) was applied to murine TCRgammadelta+ and TCRalphabeta+ intestinal IELs directly ex vivo, identifying 15,574 unique transcripts that collectively portray an "activated yet resting," Th1-skewed, cytolytic, and immunoregulatory phenotype applicable to multiple subsets of gut IELs. Expression of granzymes, Fas ligand, RANTES, prothymosin beta4, junB, RGS1, Btg1, and related molecules is high, whereas expression of conventional cytokines and high-affinity cytokine receptors is low. Differentially expressed genes readily identify heterogeneity among TCRalphabeta+ IELs, whereas differences between resident TCRgammadelta+ IELs and TCRalphabeta+ IELs are less obvious.