CD3(-)CD8(+) INTESTINAL INTRAEPITHELIAL LYMPHOCYTES (IEL) AND THE EXTRATHYMIC DEVELOPMENT OF IEL

Present evidence suggests that a majority of murine CD3(+) intraepithelial intestial lymphocytes (IEL) are etrathymically derived T cells and that these extrathymically derived IEL phenotypically expressed the CD8 homodimer (CD8 alpha alpha). Recently, CD3(-) IEL have been reported to express the recombination activating gene (RAG-1), suggesting that precursors to extrathymically derived CD3(+)CD8(+)alpha alpha IEL exist on the intestinal epithelium. To study in detail whether these CD3(-) IEL can develop into CD3(+)CD8(+)alpha alpha IEL, we analyzed the CD3(-)CD8(-) and CD3(-)CD8(+) IEL. We show that (1) CD3(-)CD8(-) IEL are mostly small, nongranular 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(+)alpha alpha IEL, respectively, appear sequentially in normal ontogeny and in bone marrow-reconstituted thymectomized radiation chimeras. In the latter, virtually all CD3(+)CD8(+)alpha alpha IEL expressed the gamma delta T cell receptor (TCR), but not the alpha beta 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(+)(gamma delta TCR)CD8+alpha alpha.