DN TCRαβ Intraepithelial T Cell Development in the Thymus

CD4 − CD8αβ − (double-negative or DN) T lymphocytes expressing a T cell receptor (TCR) composed of a variable α and β chain (DN TCRαβ + ) constitute a substantial population of mature T cells that reside mainly in the intestinal epithelium where they likely have a protective as well as regulatory role to preserve the integrity of this critical barrier. DN TCRαβ + intraepithelial T cells develop in the thymus as mature effector/memory cells with variable major histocompatibility complex (MHC) restriction ranging from classical MHC class I or II to various nonclassical MHC class I specificities. DN TCRαβ + T cells develop in the thymus from precursors that undergo positive selection in response to strong TCR-self-antigen/MHC complex interactions called self-agonist-dependent selection. This article will describe the developmental stages and agonist selection process in the thymus as well as the characteristics of mature DN TCRαβ + intraepithelial T cells that distinguish them from conventional naive CD4 and CD8αβ TCRαβ + cells that reside in lymphoid tissues. Finally, the MHC restriction and antigen specificity of DN TCRαβ + intraepithelial T cells will be discussed in light of their unique location within the mucosal epithelial barrier of the intestine.