Intestinal intraepithelial lymphocytes include precursors committed to the T cell receptor αβ lineage

The majority of T cells develop in the thymus and exhibit well characterized phenotypic changes associated with their maturation. Previous analysis of intestinal intraepithelial lymphocytes (IEL) from nude mice and a variety of experimentally manipulated models led to the view that at least a portion of these cells represent a distinct T cell population that matures extrathymically, The IEL that are postulated to mature within the intestine include both T cell receptor (TCR) alpha beta- and gamma delta-bearing subpopulations, They can be distinguished from conventional thymically derived T cells in that they express an unusual coreceptor, a CD8 alpha homodimer, In addition, they can utilize the Fc receptor gamma-chain in place of the CD3-associated zeta-chain for TCR signaling and their maturation depends on the interleukin 2 receptor beta-chain, Moreover, TCR alpha beta(+)CD8 alpha alpha(+) IEL are not subject to conventional thymic selection processes. To determine whether CD3(-)CD8 alpha alpha(+) IEL represent precursors of T cells developing extrathymically, we examined IEL from knockout mice lacking the recombination activating gene-1 (rag-1), CD3 epsilon, or both Lck and Fyn, in which thymic T cell development is arrested. CD3(-)CD8 alpha alpha(+)CD16(+) IEL from all three mutant strains, as well as from nude mice, included cells that express pre-TCR alpha transcripts, a marker of T cell commitment. These IEL from lck(-/-)fyn(-/-) animals exhibited TCR beta-gene rearrangement. However, CD3(-)CD8 alpha alpha(+)CD16(+) IEL from epsilon-deficient mice had not undergone D beta-J beta joining, despite normal rearrangement at the TCR beta locus in thymocytes from these animals. These results revealed another distinction between thymocytes and IEL, and suggested an unexpectedly early role for CD3 epsilon in IEL maturation.