CD69 prevents PLZFhi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation

Nat Commun. 2018 Sep 14;9(1):3749. doi: 10.1038/s41467-018-06283-1.


While CD69 may regulate thymocyte egress by inhibiting S1P1 expression, CD69 expression is not thought to be required for normal thymocyte development. Here we show that CD69 is in fact specifically required for the differentiation of mature NKT2 cells, which do not themselves express CD69. Mechanistically, CD69 expression is required on CD24+ PLZFhi innate precursors for their retention in the thymus and completion of their differentiation into mature NKT2 cells. By contrast, CD69-deficient CD24+ PLZFhi innate precursors express S1P1 and prematurely exit the thymus, while S1P1 inhibitor treatment of CD69-deficient mice retains CD24+ PLZFhi innate precursors in the thymus and restores NKT2 cell differentiation. Thus, CD69 prevents S1P1 expression on CD24+ PLZFhi innate precursor cells from aborting NKT2 differentiation in the thymus. This study reveals the importance of CD69 to prolong the thymic residency time of developing immature precursors for proper differentiation of a T cell subset.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Antigens, Differentiation, T-Lymphocyte / genetics*
  • CD24 Antigen / metabolism
  • Cell Differentiation
  • Gene Expression Regulation
  • Lectins, C-Type / genetics*
  • Lymphopoiesis / genetics*
  • Mice
  • Mice, Knockout
  • Natural Killer T-Cells / cytology*
  • Natural Killer T-Cells / metabolism
  • Promyelocytic Leukemia Zinc Finger Protein / metabolism
  • Receptors, Lysosphingolipid / genetics*
  • Sphingosine-1-Phosphate Receptors
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / metabolism
  • Thymocytes / cytology*
  • Thymocytes / metabolism


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD24 Antigen
  • CD69 antigen
  • Cd24a protein, mouse
  • Lectins, C-Type
  • Promyelocytic Leukemia Zinc Finger Protein
  • Receptors, Lysosphingolipid
  • S1pr1 protein, mouse
  • Sphingosine-1-Phosphate Receptors
  • Zbtb16 protein, mouse