Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: roles of IL-2 versus IL-15

Eur J Immunol. 2008 Jun;38(6):1664-76. doi: 10.1002/eji.200838190.


Regulatory T cell deficiency is evident in patients with lupus, but the casual [corrected] relationship and underlying mechanism leading to Treg deficiency are unclear. We analyzed the Treg profile, induction and functions of Treg in a lupus mouse model. A characteristic age-dependent biphasic change of Treg frequency was observed in the MRL/lpr mice, which developed a spontaneous lupus-like disease. After an early increase, Treg frequency in the peripheral lymphoid organs rapidly declined with age. Functionally, Treg from both young and old MRL/lpr mice were fully competent in suppressing the wild-type MRL/+ T effector cell (Teff) responses. Adoptive transfer of MRL/+ Treg markedly suppressed clinical disease in the MRL/lpr mice. We demonstrated that the reduced Treg frequency was a result of insufficient peripheral Treg expansion due to defective MRL/lpr Teff in IL-2 production, and the associated defects in dendritic cells, which could be fully restored by exogenous IL-2. In the absence of IL-2, MRL/lpr Teff but not MRL/lpr Treg were highly responsive to IL-15 and could expand rapidly due to enhanced IL-15R expression and IL-15 synthesis. These findings thus provide a clear causal relationship and immunological mechanism underlying Treg deficiency and systemic autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Age Factors
  • Animals
  • Antigen-Presenting Cells / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Proliferation / drug effects
  • Cytokines / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Female
  • Interferon-gamma / metabolism
  • Interleukin-15 / blood
  • Interleukin-15 / metabolism*
  • Interleukin-15 / pharmacology
  • Interleukin-2 / metabolism*
  • Interleukin-2 / pharmacology
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / pathology
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Proteinuria / urine
  • Receptors, Interleukin-15 / metabolism
  • Skin / drug effects
  • Skin / metabolism
  • Skin / pathology
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology


  • Cytokines
  • Interleukin-15
  • Interleukin-2
  • Receptors, Interleukin-15
  • Interferon-gamma