Thymic differentiation of TCRαβ+ CD8αα+ IELs

Intraepithelial lymphocytes (IELs) contain several subsets, but the origin of the T-cell receptor (TCR)alpha beta(+) CD8 alpha alpha(+) IELs has been particularly controversial. Here we provide a synthesis, based on recent work, that attempts to unify the divergent views. The intestine has a primordial function in lymphopoiesis, and precursors with the potential to differentiate into T cells are found both in the epithelium and underlying lamina propria. Moreover, the thymus has been reported to export cells to the intestine that are not fully differentiated. TCR alpha beta(+) CD8 alpha alpha(+) IELs can differentiate in the intestine from each of these sources, but in normal euthymic mice, the thymus appears to be the major source for TCR alpha beta(+) CD8 alpha alpha(+) IELs. This unique IEL subset is a self-reactive population that requires exposure to self-agonists for selection in the thymus, similar to other regulatory T-cell populations. IELs transition through a double-positive (DP) intermediate in the thymus, but they originate from a subset of the DP cells that can be identified by its expression of CD8 alpha alpha homodimers. The agonist-selected cells in the thymus are TCR beta(+) but CD4 and CD8 double negative. The evidence suggests that reacquired expression of CD8 alpha alpha and downregulation of CD5 occur after thymus export, perhaps in the intestine under the influence of interleukin-15. As a result of agonist exposure, a new gene expression program is activated. Therefore, the increased understanding of the developmental origin of TCR alpha beta(+) CD8 alpha alpha(+) IELs may help us to understand how they participate in immune regulation and protection in the intestine.