Intraepithelial lymphocytes: exploring the Third Way in immunology

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.