Developmental features and unique characteristics of peptide-specific PLZF+ innate-like T cells in mice

Ahmed Hassan, Nico Heise, Anja Schimrock, Stefanie Willenzon, Inga Ravens, Reinhold Förster and Hristo Georgiev ()
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Ahmed Hassan: Hannover Medical School
Nico Heise: Hannover Medical School
Anja Schimrock: Hannover Medical School
Stefanie Willenzon: Hannover Medical School
Inga Ravens: Hannover Medical School
Reinhold Förster: Hannover Medical School
Hristo Georgiev: Hannover Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Peptide-specific PLZF+ innate-like T (PILT) cells are a member of the innate-like T cell family utilizing a diverse set of T cell receptor (TCR) Vβ chains. Yet there are no present studies providing clues into the developmental features of PILT cells at a transcriptome level. Here, we performed single-cell transcriptomic analyses of PILT cells and compared them to other members of the innate-like T cell family. We show that PILT cells share similar transcriptional profiles and overlapping developmental trajectories with invariant Natural Killer T (iNKT) cells. However, in contrast to iNKT cells, PILT cells display a polyclonal TCR repertoire closely resembling the one of conventional CD8 T cells, inferring MHC I restriction and a broader range of antigen specificity. We further show that artificial thymic organoid cultures (ATOC) support selection and development of PILT cells in vitro exhibiting similar transcriptional profiles to their counterparts maturing in the thymus. Moreover, using an “on-time” TCR retrogenic ATOC system, we provide evidence for an instructive role of TCR specificity in PILT cell lineage commitment and functional differentiation. Altogether, our findings provide further insights into the PILT cells unique characteristics and molecular mechanisms governing their development.

Date: 2025
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DOI: 10.1038/s41467-025-60617-4

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