Abstract
In designating the thymic origin of the cells, the T in T cell seems simple enough, and the impressive unfolding of how the differentiation and selection of conventional CD4 and CD8 T cells are supported by the uniquely capable thymic stroma seems prima facie to leave little left to uncover. But, as the initial uncovering of T-cell receptor (TCR) gamma-chain genes forewarned, there are myriad "unconventional T cell" subtypes whose development is not easily explained by current understanding. Such cells, either TCR alphabeta(+) or TCR gamma delta(+), rarely express either CD4 (a coreceptor for major histocompatibility complex (MHC) II) or CD8 alphabeta (a coreceptor for MHC I).(2) Instead, they are CD4, CD8 double-negative (DN) or express a homomeric CD8 alpha alpha molecule. However, rather than being mere fringe players, worthy only of "page 2, column 3,"(3) these unconventional T cells compose a substantial fraction of perhaps the most abundant and most active T cells in the body--the intraepithelial lymphocytes (IELs)--that populate several body surfaces, including the gut. There, they seemingly contribute to the physiologic homeostasis that embraces epithelial integrity, the measured immune response to commensals, and the adaptive tolerance toward self-antigens. When this homeostasis is disrupted, IELs may also contribute to inflammatory and wound-healing responses. Given this, a strong interest in their origin is appropriate.