CD3−CD8+ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL

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Abstract
Present evidence suggests that a majority of murine CD3+ intraepithelial intestinal lymphocytes (IEL) are extrathymically derived T cells and that these extrathymically derived IEL phenotypically express the CD8 homodimer (CD8αα). Recently, CD3− IEL have been reported to express the recombination activating gene (RAG‐1), suggesting that precursors to extrathymically derived CD3+CD8+αα IEL exist on the intestinal epithelium. To study in detail whether these CD3− IEL can develop into CD3+CD8+αα IEL, we analyzed the CD3− IEL subset and found that it can be separated into two subsets, namely CD3−CD8− and CD3−CD8+ IEL. We show that (1) CD3−CD8− IEL are mostly small, non‐granular and phenotypically Pgp‐1+ IL‐2R+ B220−, while CD3−CD8+ IEL are mostly large, granular and phenotypically Pgp‐1− IL‐2R+ B220+, (2) CD3−‐CD8+ IEL express the RAG‐1 gene, and (3) CD3−CD8−, CD3−CD8+ and CD3+CD8+αα IEL, respectively, appear sequentially in normal ontogeny and in bone marrow‐reconstituted thymectomized radiation chimeras. In the latter, virtually all CD3+CD8+αα IEL expressed the γδ T cell receptor (TCR), but not the αβ TCR. From this and what is presently known about T cell development, we propose that CD3−CD8+ IEL are an intermediate in extrathymic IEL development and that the development of extrathymically derived IEL occurs at the intestinal epithelium from CD3−CD8− to CD3−CD8+ to CD3+(γδ TCR)CD8+αα.