A novel pathway of thymus-directed T lymphocyte maturation

Recent evidence has indicated that the intestinal epithelium may be a major extrathymic site of T cell production. However, which of the multiple intestinal intraepithelial lymphocyte (IEL) subsets are extrathymic in origin has been controversial. We now report that the thymus is an integral component of IEL maturation and is required for a novel two-stage process of T cell production. Thus, in neonatally thymectomized mice TCR-gamma delta IELs were depleted and some TCR-alpha beta IELs were of an immature phenotype. Thymus grafting experiments revealed that all TCR-gamma delta and TCR-alpha beta IEL subsets could be thymus-derived, including TCR-alpha beta cells lacking Thy1 and CD8 beta. In utero anti-TCR-gamma delta mAb treatments resulted in depletion of gamma delta IEL without subsequent re-emergence of this subset in adulthood, whereas anti-TCR-alpha beta mAb treatment only marginally reduced the alpha beta IEL subset. These findings suggest that TCR-alpha beta and TCR-gamma delta IELs arose at distinct developmental stages. Overall, the results indicate that some IEL precursors are thymus-derived but require further thymic influence to mature in the periphery.