Progenies of fetal thymocytes are the major source of CD4-CD8+ alpha alpha intestinal intraepithelial lymphocytes early in ontogeny.
Present literature supports the view of an extrathymic origin for the subset of intestinal intraepithelial lymphocytes (IEL) that express the CD4-CD8+ alpha alpha phenotype. This subset would include virtually all T cell receptor (TCR) gamma delta IEL and a portion of TCR alpha beta IEL. However, these reports do not exclude the possibility that some CD4-CD8+ alpha alpha IEL are actually thymically derived. To clarify this issue, we examined the IEL day 3 neonatally thymectomized (NTX) mice. NTX resulted in as much as 80% reduction in total TCR gamma delta IEL and in a nearly complete elimination of TCR alpha beta CD4-CD8+ alpha alpha IEL early in ontogeny (3- to 5-week-old mice). The thymus dependency of TCR gamma delta IEL and TCR alpha beta CD4-CD8+ IEL was less prominent in older mice (7- to 10-week-old mice), as the total number of these IEL increased in NTX mice, but still remained severalfold less than that in euthymic mice. Furthermore, we demonstrate, by grafting the fetal thymus of CBF1 (H-2b/d) mice under the kidney capsule of congenitally nude athymic mice of BALB/c background (H-2d), that a substantial number of TCR gamma delta IEL and TCR alpha beta CD4-CD8+ alpha alpha IEL can be thymically derived (H-2b+). In contrast, but consistent with our NTX data, grafting of adult thymi into nude mice generated virtually no TCR gamma delta IEL and relatively less TCR alpha beta CD4-CD8+ alpha alpha IEL than did the grafting of fetal thymi. These results suggest that the thymus is the major source of TCR gamma delta and TCR alpha beta CD4-CD8+ alpha alpha IEL early in ontogeny, but that the extrathymic pathway is probably the major source of these IEL later in ontogeny. A reassessment of the theory that most CD4-CD8 IEL are extrathymically derived is needed.