In vivo blockade of T cell development reveals alternative pathways for generation of intraepithelial lymphocytes in mice.

Intraepithelial lymphocytes (IELs) are resident cells localized within the intestinal epithelia and play an important role in regulating gut inflammations and host defense against pathogens. CD8α TCRαβ IELs are heterogeneous populations that are generated from T cell precursors including CD4 CD8α double-negative (DN) cells and CD4 CD8α double-positive (DP) cells. However, developmental pathways of TCRαβ IELs remained unclear. To gain insight into the mechanisms, we generated mice (Bcl11b mice) that lack thymic precursors (DN CD5 TCRβ cells) for CD4 CD8αα TCRαβ IELs. Unexpectedly, we found that, in the absence of the precursors in thymi of Bcl11b mice, CD4 CD8αα TCRαβ IELs were still present in the intestine though the number was reduced. Adoptive transfer experiment showed that their precursors were highly enriched in CD8α TCRβ thymocytes. The CD4 CD8αα TCRαβ IELs in Bcl11b mice are distinguished by Thy1.2 expression and are indeed present in WT mice. Taken together, our study reveal a novel developmental pathway for CD8αα TCRαβ IELs.