The human fetal thymus generates effector invariant ?d T cells in a Lin28b-dependent manner

In the mouse thymus, invariant ?d T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming can occur in human is not known. Here we analyzed human fetal and post-natal ?d thymocytes and investigated the role of hematopoietic-stem-and-precursor-cells (HSPC) in the generation of human ?d T cells. Unlike post-natal ?d thymocytes, fetal ?d thymocytes were functionally programmed (e.g. IFN?, granzymes), expressed low levels of terminal-deoxynucleotidyl-transferase (TdT) and were highly enriched for invariant/public germline-encoded CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY and TRDV1-TRDD3-CALGELGD, previously shown to be expanded in cytomegalovirus infection) composed of short-homology-repeat-containing gene segments. Furthermore, these unique characteristics were due to an intrinsic property of fetal HSPC caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in a HSPC/Lin28b-dependent manner, invariant ?d T cells with programmed effector functions. Overall design: analysis of human fetal and post-natal ?d thymocytes and the role of hematopoietic-stem-and-precursor-cells (HSPC) in the generation of human ?d T cells.