Thymic epithelial cells require lipid kinase Vps34 for CD4 but not CD8 T cell selection

J Exp Med. 2022 Oct 3;219(10):e20212554. doi: 10.1084/jem.20212554. Epub 2022 Aug 23.


The generation of a functional, self-tolerant T cell receptor (TCR) repertoire depends on interactions between developing thymocytes and antigen-presenting thymic epithelial cells (TECs). Cortical TECs (cTECs) rely on unique antigen-processing machinery to generate self-peptides specialized for T cell positive selection. In our current study, we focus on the lipid kinase Vps34, which has been implicated in autophagy and endocytic vesicle trafficking. We show that loss of Vps34 in TECs causes profound defects in the positive selection of the CD4 T cell lineage but not the CD8 T cell lineage. Utilizing TCR sequencing, we show that T cell selection in conditional mutants causes altered repertoire properties including reduced clonal sharing. cTECs from mutant mice display an increased abundance of invariant chain intermediates bound to surface MHC class II molecules, indicating altered antigen processing. Collectively, these studies identify lipid kinase Vps34 as an important contributor to the repertoire of selecting ligands processed and presented by TECs to developing CD4 T cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CD8 Antigens
  • CD8-Positive T-Lymphocytes*
  • Class III Phosphatidylinositol 3-Kinases / metabolism*
  • Epithelial Cells
  • Lipids
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Antigen, T-Cell
  • Thymus Gland


  • CD8 Antigens
  • Lipids
  • Receptors, Antigen, T-Cell
  • Class III Phosphatidylinositol 3-Kinases
  • PIK3C3 protein, mouse