Single-cell profiling identifies a novel human polyclonal unconventional T cell lineage

• Published in: The Journal of experimental medicine Vol. 220; no. 6
• Main Authors: Billiet, Lore, De Cock, Laurenz, Sanchez Sanchez, Guillem, Mayer, Rupert L, Goetgeluk, Glenn, De Munter, Stijn, Pille, Melissa, Ingels, Joline, Jansen, Hanne, Weening, Karin, Pascal, Eva, Raes, Killian, Bonte, Sarah, Kerre, Tessa, Vandamme, Niels, Seurinck, Ruth, Roels, Jana, Lavaert, Marieke, Van Nieuwerburgh, Filip, Leclercq, Georges, Taghon, Tom, Impens, Francis, Menten, Björn, Vermijlen, David, Vandekerckhove, Bart
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 05-06-2023
• Subjects: Adult; Cell Differentiation; Cell Lineage; Humans; Innate Immunity and Inflammation; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - metabolism; T-Lymphocytes - metabolism; Thymus Gland
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20220942

In the human thymus, a CD10+ PD-1+ TCRαβ+ differentiation pathway diverges from the conventional single positive T cell lineages at the early double-positive stage. Here, we identify the progeny of this unconventional lineage in antigen-inexperienced blood. These unconventional T cells (UTCs) in thymus and blood share a transcriptomic profile, characterized by hallmark transcription factors (i.e., ZNF683 and IKZF2), and a polyclonal TCR repertoire with autoreactive features, exhibiting a bias toward early TCRα chain rearrangements. Single-cell RNA sequencing confirms a common developmental trajectory between the thymic and blood UTCs and clearly delineates this unconventional lineage in blood. Besides MME+ recent thymic emigrants, effector-like clusters are identified in this heterogeneous lineage. Expression of Helios and KIR and a decreased CD8β expression are characteristics of this lineage. This UTC lineage could be identified in adult blood and intestinal tissues. In summary, our data provide a comprehensive characterization of the polyclonal unconventional lineage in antigen-inexperienced blood and identify the adult progeny.