Development and function of invariant natural killer T cells producing T(h)2- and T(h)17-cytokines

PLoS Biol. 2012 Feb;10(2):e1001255. doi: 10.1371/journal.pbio.1001255. Epub 2012 Feb 7.


There is heterogeneity in invariant natural killer T (iNKT) cells based on the expression of CD4 and the IL-17 receptor B (IL-17RB), a receptor for IL-25 which is a key factor in T(H)2 immunity. However, the development pathway and precise function of these iNKT cell subtypes remain unknown. IL-17RB⁺iNKT cells are present in the thymic CD44⁺/⁻ NK1.1⁻ population and develop normally even in the absence of IL-15, which is required for maturation and homeostasis of IL-17RB⁻iNKT cells producing IFN-γ. These results suggest that iNKT cells contain at least two subtypes, IL-17RB⁺ and IL-17RB⁻ subsets. The IL-17RB⁺iNKT subtypes can be further divided into two subtypes on the basis of CD4 expression both in the thymus and in the periphery. CD4⁺ IL-17RB⁺iNKT cells produce T(H)2 (IL-13), T(H)9 (IL-9 and IL-10), and T(H)17 (IL-17A and IL-22) cytokines in response to IL-25 in an E4BP4-dependent fashion, whereas CD4⁻ IL-17RB⁺iNKT cells are a retinoic acid receptor-related orphan receptor (ROR)γt⁺ subset producing T(H)17 cytokines upon stimulation with IL-23 in an E4BP4-independent fashion. These IL-17RB⁺iNKT cell subtypes are abundantly present in the lung in the steady state and mediate the pathogenesis in virus-induced airway hyperreactivity (AHR). In this study we demonstrated that the IL-17RB⁺iNKT cell subsets develop distinct from classical iNKT cell developmental stages in the thymus and play important roles in the pathogenesis of airway diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchial Hyperreactivity / immunology
  • Bronchial Hyperreactivity / metabolism
  • Bronchial Hyperreactivity / pathology
  • Bronchial Hyperreactivity / virology
  • Cells, Cultured
  • Cytokines / metabolism*
  • Flow Cytometry
  • Gene Expression Profiling
  • Immunophenotyping
  • Liver / pathology
  • Lung / immunology
  • Lung / pathology
  • Lung / virology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Natural Killer T-Cells / pathology
  • Natural Killer T-Cells / physiology*
  • Organ Specificity
  • Receptors, Interleukin-17 / genetics
  • Receptors, Interleukin-17 / metabolism
  • Respiratory Syncytial Virus Infections / immunology
  • Respiratory Syncytial Virus Infections / pathology
  • Spleen / pathology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / physiology*
  • Th17 Cells / pathology
  • Th17 Cells / physiology
  • Th2 Cells / pathology
  • Th2 Cells / physiology
  • Thymus Gland / pathology
  • Tissue Culture Techniques


  • Cytokines
  • Receptors, Interleukin-17