Whence the intestinal intraepithelial lymphocyte?

O ne of the most widely accepted principles of immunobiology is that lymphocytes with phenotypic and functional properties o f T cells develop from hematopoietic precursors during a requisite period of intrathymic maturation. This developmental stage appears to prepare T cells for their ability to recognize tissue-borne foreign antigens, and to render the peripheral T cell repertoire tolerant to normal host tissue antigens (1, 2). This is not to say that lymphocytes with properties of T cells cannot develop extrathymically, but rather that when immunologists have sought evidence for extrathymic pathways of T cell development, little has been found. Now, however, considerable empirical evidence supports the likelihood that T cells in the small intestine of mice, the intestinal intraepithelial lymphocytes (IELs), have genuine extrathymic origins (3-9). Yet, many aspects of that process remain highly contentious, and the debate involves issues that are central to how the gastrointestinal tract--one of the largest barriers of foreign antigen invasion--maintains its immunological integrity. Curiously, the intestinal IELs were one of the first discrete populations of lymphoid ceils to be identified in mammalian species (10). However, studies of that lymphocyte population were quickly superseded by detailed exploration into lymphocyte biology using more accessible pools of cells in the spleen and lymph nodes of mice, and in the blood of humans. In fact, the intestinal epithelium with its collection of eclectic T cells containing no less than ten distinct phenotypic subsets (11), many with novel functional properties (12, 13), is still occasionally regarded as little more than a graveyard of dying and effete cells. The rejuvenated interest in the IELs can be attributed to several factors, not the least of which is the potential extrathymic nature of those cells, and the identification of IELs as a major pool of peripheral ~8 T cells (14). Evidence for the former comes from traditional experimental approaches used by immunologists to delineate pathways of T cell development, including studies in congenitally-athymic nude mice, in mice rendered athymic as neonates (neonatally thymectomized [NTX] mice), and in adult athymic radiation chimeras. The basic findings from those studies have been consistent, yet perplexing. Simply summarized, they are: (0 IELs in adult athymic chimeras are most similar, phenotypically, to IELs found in normal unmanipulated mice; these include both TC1KoL[3 and TClKy8 IELs as well as CD8ot0~ and CD8o~ subsets (4, 8, 9); (i 0 IELs in nude mice strongly favor the TC1K~/8 and CD8~xo~ lineage(s), although some age-dependent increases occur in the numbers ot[3