Highlights d Unbiased scRNA-seq on thymic iNKT reveals discrete subsets in iNKT1 and iNKT2 d Transcriptomically defined iNKT2 cells comprise precursors to iNKT1 and iNKT17 d Most of thymic iNKT subsets seem to have the potential to egress the thymus d The transcription cofactor FHL2 controls specification of the iNKT1 effector fate

Highlights d Unbiased scRNA-seq on thymic iNKT reveals discrete subsets in iNKT1 and iNKT2 d Transcriptomically defined iNKT2 cells comprise precursors to iNKT1 and iNKT17 d Most of thymic iNKT subsets seem to have the potential to egress the thymus d The transcription cofactor FHL2 controls specification of the iNKT1 effector fate

No abstract

CD1d-restricted invariant NKT (iNKT) cells are innate-like T cells that respond to glycolipids, a class of Ags that are invisible to conventional T cells. iNKT cells develop in the thymus where they receive strong "agonist" TCR signals. During their ontogeny, iNKT cells differentiate into discrete iNKT1, iNKT2, and iNKT17 effector subsets akin to helper CD4 T cells. In this study, we found that transgenic (Tg) expression of the canonical Va14-Ja18 TCRa-chain at the double-positive thymocyte stage led to premature iNKT cell development and a cell-intrinsic bias toward iNKT2 cells, due to increased TCR signaling upon selection. Consistent with the strong iNKT2 bias, innate memory CD8 + T cells were found in greater numbers in Va14 Tg mice, whereas the prevalence of mucosa-associated invariant T cells was reduced. iNKT cells from Va14 Tg mice were hyporesponsive to stimulation by their cognate Ag a-galactosylceramide. Finally, Va14 Tg mice displayed increased B16F10 melanoma tumor growth compared with wild-type mice. This study reveals some of the limitations of Va14 Tg mice and warrants the cautious interpretation of past and future findings using this mouse model. ImmunoHorizons, 2020, 4: 797-808.

The vast majority of studies on T cell biology in tumor immunity have focused on peptide-reactive conventional T cells that are restricted to polymorphic major histocompatibility complex molecules. However, emerging evidence indicated that unconventional T cells, including γδ T cells, natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are also involved in tumor immunity. Unconventional T cells span the innate–adaptive continuum and possess the unique ability to rapidly react to nonpeptide antigens via their conserved T cell receptors (TCRs) and/or to activating cytokines to orchestrate many aspects of the immune response. Since unconventional T cell lineages comprise discrete functional subsets, they can mediate both anti- and protumoral activities. Here, we review the current understanding of the functions and regulatory mechanisms of protumoral unconventional T cell subsets in the tumor environment. We also discuss the therapeutic potential of these deleterious subsets in solid cancers and why further feasibility studies are warranted.