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

Coreceptor CD4 and CD8 alpha beta double-negative (DN) TCR alpha beta(+) intraepithelial T cells, although numerous, have been greatly overlooked and their contribution to the immune response is not known. Here we used T cell receptor (TCR) sequencing of single cells combined with retrogenic expression of TCRs to study the fate and the major histocompatibility complex (MHC) restriction of DN TCR alpha beta(+) intraepithelial T cells. The data show that commitment of thymic precursors to the DN TCR alpha beta(+) lineage is imprinted by their TCR specificity. Moreover, the TCRs they express display a diverse and unusual pattern of MHC restriction that is nonoverlapping with that of CD4(+) or CD8 alpha beta(+) T cells, indicating that they sense antigens that are not recognized by the conventional T cell subsets. The new insights indicate that DN TCR alpha beta(+) T cells form a third lineage of TCR alpha beta T lymphocytes expressing a variable TCR repertoire, which serve nonredundant immune functions.