Thymus influences the development of extrathymically derived intestinal intraepithelial lymphocytes

Overwhelming evidence suggests that the majority of murine small intestinal intraepithelial lymphocytes (IEL) are extrathymically derived. These IEL include those with T cell receptor (TCR) gamma delta and some TCR alpha beta (CD8 alpha alpha and Thy-1-). In contrast, congenitally athymic nude mice have low numbers of gamma delta TCR IEL as well as very few alpha beta TCR IEL, far less than that would be expected if one assumes that gamma delta TCR IEL and alpha beta TCR (CD8 alpha alpha and Thy-1-) IEL in euthymic mice are extrathymically derived. To examine this discrepancy, we followed extrathymic IEL differentiation in IEL of day 3-thymectomized (NTX) mice as another athymic mouse model and found that gamma delta TCR IEL and extrathymically derived alpha beta TCR IEL in NTX mice are markedly reduced, almost to the level of nude mice. We further show that it is probably the absence of a thymic stroma that is responsible for the lower amounts of extrathymically derived IEL in nude mice, as the low amounts can be corrected to euthymic levels by syngeneic fetal thymus grafting but not by direct injection of F1 thymocytes. Lastly, unlike TCR/CD3+ extrathymically derived IEL, we noted a large proportion of extrathymic CD3-CD8- and CD3-CD8+ IEL; they were threefold more frequent in nude and NTX than in euthymic mice. This suggests that the thymus influences extrathymically derived IEL in its development from CD3- to CD3+ at the small intestinal epithelium.