ABSTRACT T cells develop by an obligatory passage through the thymus. During that excursion, immature bone marrow- derived T cell precursors are prepared to recognize major histocompatibility complex-associated peptide antigens on tissue surfaces, and are depleted of overtly autoreactive T cells. Cells that meet those criteria are seeded into peripheral lymphoid organs of the spleen, lymph nodes, and blood. Studies over the past two decades now provide compelling evidence that, in contrast to T cells elsewhere in the organism, as much as 70-80% of the T cells in the small intestine of mice — the intraepithelial lymphocytes [IELs] — are extrathymic T cells that mature locally within the intestine from bone marrow progenitors. Those IELs bear differences in phenotypic markers compared to conventional thymus-derived T cells, most notably in the expression of a CD8αα homodimer in conjunction with either T cell receptor [TCR]αβ or TCRγδ. Moreover, notable differences exist in the nature of intracellular signaling and cytokine and growth- promoting requirements of extrathymic IELs. Although IELs are present in athymic animals [i.e., congenitally- athymic nude mice, neonatally-thymectomized mice, and adult athymic radiation chimeras], the role of the thymus in the overall process of IEL development remains a controversial topic. In this review, these and other aspects of IEL development are discussed, and the composition and distribution of IELs in normal animals is shown to reflect a complex series of multiple interactive events linked to specific types of IEL precursors, the intestinal epithelium, and the influence of thymus-associated factors.
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