Leukocytes in the intestinal epithelium: an unusual immunological compartment revisited

Intraepithelial lymphocytes (IEL) are characterized by significant heterogeneity in morphology, surface antigen expression, and function. Although IEL can express T cell markers including the T cell receptor (TcR), their relationship to peripheral T cells is not clear. The finding of IEL in athymic nude mice first suggested that a number of IEL may be thymic-independent. The identification of the gamma/delta TcR heterodimer on IEL further suggested that these cells are part of a distinct population of epithelial-associated lymphocytes, many of which express the gamma/delta TcR. We review the nature of the V gamma gene usage in IEL and highlight the differences between different gamma/delta T cell populations. The thymic independent nature of these gamma/delta cells is discussed and compared to that of the alpha/beta TcR expressing IEL. The finding that some alpha/beta IEL can develop independent of thymic processing suggests that IEL are characterized by a unique collection of T cells that may undergo differentiation within the intestinal compartment. The ability to distinguish T-dependent from T-independent IEL raises the possibility of identifying the functional nature of these two IEL lineages. We propose that the ability of IEL to potentially undergo repertoire selection in the intestine could allow for the development of mucosal T cells uniquely adapted to function in this environment.