Molecular mechanisms of lineage decisions in metabolite-specific T cells

Nat Immunol. 2019 Sep;20(9):1244-1255. doi: 10.1038/s41590-019-0465-3. Epub 2019 Aug 20.


Mucosal-associated invariant T cells (MAIT cells) recognize the microbial metabolite 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) presented by the MHC class Ib molecule, MR1. MAIT cells acquire effector functions during thymic development, but the mechanisms involved are unclear. Here we used single-cell RNA-sequencing to characterize the developmental path of 5-OP-RU-specific thymocytes. In addition to the known MAIT1 and MAIT17 effector subsets selected on bone-marrow-derived hematopoietic cells, we identified 5-OP-RU-specific thymocytes that were selected on thymic epithelial cells and differentiated into CD44- naive T cells. MAIT cell positive selection required signaling through the adapter, SAP, that controlled the expression of the transcription factor, ZBTB16. Pseudotemporal ordering of single cells revealed transcriptional trajectories of 5-OP-RU-specific thymocytes selected on either thymic epithelial cells or hematopoietic cells. The resulting model illustrates T cell lineage decisions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Lineage / immunology*
  • Histocompatibility Antigens Class I / metabolism
  • Hyaluronan Receptors / metabolism
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • Minor Histocompatibility Antigens / metabolism
  • Mucosal-Associated Invariant T Cells / cytology*
  • Mucosal-Associated Invariant T Cells / immunology*
  • Promyelocytic Leukemia Zinc Finger Protein / biosynthesis
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Ribitol / analogs & derivatives*
  • Ribitol / immunology
  • Sequence Analysis, RNA
  • Signaling Lymphocytic Activation Molecule Family / metabolism
  • Thymocytes / cytology*
  • Thymocytes / immunology*
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Uracil / analogs & derivatives*
  • Uracil / immunology


  • 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil
  • Cd44 protein, mouse
  • Histocompatibility Antigens Class I
  • Hyaluronan Receptors
  • Minor Histocompatibility Antigens
  • Mr1 protein, mouse
  • Promyelocytic Leukemia Zinc Finger Protein
  • Receptors, Antigen, T-Cell, alpha-beta
  • Signaling Lymphocytic Activation Molecule Family
  • Slamf6 protein, mouse
  • Zbtb16 protein, mouse
  • Ribitol
  • Uracil