IL-15 regulates homeostasis and terminal maturation of NKT cells

J Immunol. 2011 Dec 15;187(12):6335-45. doi: 10.4049/jimmunol.1003965. Epub 2011 Nov 14.

Abstract

Semi-invariant NKT cells are thymus-derived innate-like lymphocytes that modulate microbial and tumor immunity as well as autoimmune diseases. These immunoregulatory properties of NKT cells are acquired during their development. Much has been learned regarding the molecular and cellular cues that promote NKT cell development, yet how these cells are maintained in the thymus and the periphery and how they acquire functional competence are incompletely understood. We found that IL-15 induced several Bcl-2 family survival factors in thymic and splenic NKT cells in vitro. Yet, IL-15-mediated thymic and peripheral NKT cell survival critically depended on Bcl-x(L) expression. Additionally, IL-15 regulated thymic developmental stage 2 to stage 3 lineage progression and terminal NKT cell differentiation. Global gene expression analyses and validation revealed that IL-15 regulated Tbx21 (T-bet) expression in thymic NKT cells. The loss of IL-15 also resulted in poor expression of key effector molecules such as IFN-γ, granzyme A and C, as well as several NK cell receptors, which are also regulated by T-bet in NKT cells. Taken together, our findings reveal a critical role for IL-15 in NKT cell survival, which is mediated by Bcl-x(L), and effector differentiation, which is consistent with a role of T-bet in regulating terminal maturation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cell Lineage / genetics
  • Cell Lineage / immunology
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Homeostasis / genetics
  • Homeostasis / immunology*
  • Interleukin-15 / deficiency
  • Interleukin-15 / genetics
  • Interleukin-15 / physiology*
  • Liver / cytology
  • Liver / immunology
  • Liver / metabolism
  • Lymphocyte Count
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Natural Killer T-Cells / cytology
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism*
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Thymus Gland / metabolism
  • bcl-X Protein / biosynthesis
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • IL15 protein, human
  • Interleukin-15
  • bcl-X Protein

Associated data

  • GEO/GSE32568

Grant support