αβT Cell Receptors Expressed by CD4(-)CD8αβ(-) Intraepithelial T Cells Drive Their Fate into a Unique Lineage with Unusual MHC Reactivities

Mayans S, Stepniak D, Palida SF, Larange A, Dreux J, Arlian BM, Shinnakasu R, Kronenberg M, Cheroutre H, Lambolez F.

Immunity. 2014 Aug 21;41(2):207-18. doi: 10.1016/j.immuni.2014.07.010. Epub 2014 Aug 14.

From Top Left Over: Sofia Mayans, Florence Lambolez, Dariusz Stepniak, and Hilde Cheroutre

From top, clockwise: Sofia Mayans, Florence Lambolez, Dariusz Stepniak, and Hilde Cheroutre

The development pathway and major histocompatibility complex (MHC) specificity of coreceptor CD4 and CD8αβ double negative (DN) TCRαβ+ intraepithelial T cells remained elusive for decades. In our recent study, we sequenced T cell receptors (TCR) from naturally arising DN TCRαβ+ intraepithelial T cells at a single cell level. In order to study the fate and the MHC restriction of DN TCRαβ+ intraepithelial T cells, we forced expression of cloned TCRs using a retrogenic expression strategy. The findings led to several major conclusions summarized as follows: First, the commitment of thymic precursors to the DN TCRαβ+ lineage is imprinted by their TCR specificity. Second, the precursors of the DN T cells undergo an MHC-dependent selection process in the thymus that requires strong TCR signaling events. Finally, the TCRs they express display a diverse and unusual pattern of MHC restriction that is non-overlapping with that of CD4+ or CD8αβ+ T cells, indicating that they sense antigens that are not recognized by the conventional T cell subsets. The new insights indicate that DN TCRαβ+ intraepithelial T cells form a third lineage of TCRαβ+ T lymphocytes that develop in the thymus and express a variable TCR repertoire. Due to their strategic location at the mucosal border, it is highly possible that DN TCRαβ+ intraepithelial T cells are designed to play a nonredundant role in immune surveillance and protection. PubMed:25131531