The thymic microenvironment differentially regulates development and trafficking of invariant NKT cell sublineages

J Immunol. 2014 Dec 15;193(12):5960-72. doi: 10.4049/jimmunol.1401601. Epub 2014 Nov 7.


The regulatory role of the thymic microenvironment during trafficking and differentiation of the invariant NKT (iNKT) cell lineage remains poorly understood. In this study, we show that fractalkine receptor expression marks emigrating subpopulations of the NKT1, NKT2, and NKT17 sublineages in the thymus and peripheral organs of naive mice. Moreover, NKT1 sublineage cells can be subdivided into two subsets, namely NKT1(a) and NKT1(b), which exhibit distinct developmental and tissue-specific distribution profiles. More specifically, development and trafficking of the NKT1(a) subset are selectively dependent upon lymphotoxin (LT)α1β2-LTβ receptor-dependent differentiation of thymic stroma, whereas the NKT1(b), NKT2, and NKT17 sublineages are not. Furthermore, we identify a potential cellular source for LTα1β2 during thymic organogenesis, marked by expression of IL-7Rα, which promotes differentiation of the NKT1(a) subset in a noncell-autonomous manner. Collectively, we propose a mechanism by which thymic differentiation and retention of the NKT1 sublineage are developmentally coupled to LTα1β2-LTβ receptor-dependent thymic organogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Movement*
  • Cellular Microenvironment*
  • Cluster Analysis
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Immunohistochemistry
  • Immunophenotyping
  • Interleukin-7 Receptor alpha Subunit / genetics
  • Interleukin-7 Receptor alpha Subunit / metabolism
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphotoxin alpha1, beta2 Heterotrimer / metabolism
  • Lymphotoxin beta Receptor / metabolism
  • Lymphotoxin-beta / deficiency
  • Male
  • Mice
  • Mice, Transgenic
  • Natural Killer T-Cells / cytology*
  • Natural Killer T-Cells / metabolism*
  • Phenotype
  • Pregnancy
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism
  • Receptors, HIV / genetics
  • Receptors, HIV / metabolism
  • Signal Transduction
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / metabolism*
  • Thymocytes / immunology
  • Thymocytes / metabolism
  • Thymus Gland / immunology*
  • Thymus Gland / metabolism*


  • CX3C Chemokine Receptor 1
  • Interleukin-7 Receptor alpha Subunit
  • Lymphotoxin alpha1, beta2 Heterotrimer
  • Lymphotoxin beta Receptor
  • Lymphotoxin-beta
  • Receptors, Cytokine
  • Receptors, HIV