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) αβ- and γδ-bearing subpopulations. They can be distinguished from conventional thymically derived T cells in that they express an unusual coreceptor, a CD8α homodimer. In addition, they can utilize the Fc receptor γ-chain in place of the CD3-associated ζ-chain for TCR signaling and their maturation depends on the interleukin 2 receptor β-chain. Moreover, TCRαβ(+)CD8αα(+) IEL are not subject to conventional thymic selection processes. To determine whether CD3(−)CD8αα(+) IEL represent precursors of T cells developing extrathymically, we examined IEL from knockout mice lacking the recombination activating gene-1 (rag-1), CD3ɛ, or both Lck and Fyn, in which thymic T cell development is arrested. CD3(−)CD8αα(+)CD16(+) IEL from all three mutant strains, as well as from nude mice, included cells that express pre-TCRα transcripts, a marker of T cell commitment. These IEL from lck(−/−)fyn(−/−) animals exhibited TCR β-gene rearrangement. However, CD3(−)CD8αα(+)CD16(+) IEL from ɛ-deficient mice had not undergone Dβ-Jβ joining, despite normal rearrangement at the TCRβ locus in thymocytes from these animals. These results revealed another distinction between thymocytes and IEL, and suggested an unexpectedly early role for CD3ɛ in IEL maturation.