IL-15-dependent CD8+ CD122+ T cells ameliorate experimental autoimmune encephalomyelitis by modulating IL-17 production by CD4+ T cells

Eur J Immunol. 2014 Nov;44(11):3330-41. doi: 10.1002/eji.201444675.

Abstract

Interleukin-15 (IL-15) is an inflammatory cytokine whose role in autoimmune diseases has not been fully elucidated. Th17 cells have been shown to play critical roles in experimental autoimmune encephalomyelitis (EAE) models. In this study, we demonstrate that blockade of IL-15 signaling by TMβ-1 mAb treatment aggravated EAE severity. The key mechanism was not NK-cell depletion but depletion of CD8+ CD122+ T cells. Adoptive transfer of exogenous CD8+ CD122+ T cells to TMβ-1-treated mice rescued animals from severe disease. Moreover, transfer of preactivated CD8+ CD122+ T cells prevented EAE development and significantly reduced IL-17 secretion. Naïve effector CD4+ CD25- T cells cultured with either CD8+ CD122+ T cells from wild-type mice or IL-15 transgenic mice displayed lower frequencies of IL-17A production with lower amounts of IL-17 in the supernatants when compared with production by effector CD4+ CD25- T cells cultured alone. Addition of a neutralizing antibody to IL-10 led to recovery of IL-17A production in Th17 cultures. Furthermore, coculture of CD8+ CD122+ T cells with effector CD4+ T cells inhibited their proliferation significantly, suggesting a regulatory function for IL-15 dependent CD8+ CD122+ T cells. Taken together, these observations suggest that IL-15, acting through CD8+ CD122+ T cells, has a negative regulatory role in reducing IL-17 production and Th17-mediated EAE inflammation.

Keywords: CD8+CD122+ T cells; Experimental autoimmune encephalomyelitis; Interleukin-15; Interleukin-17; Multiple sclerosis.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Coculture Techniques
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Interleukin-15 / antagonists & inhibitors
  • Interleukin-15 / immunology*
  • Interleukin-17 / biosynthesis*
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukin-2 Receptor beta Subunit / immunology
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / transplantation
  • Lymphocyte Activation / immunology
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Signal Transduction / immunology
  • Th17 Cells / cytology
  • Th17 Cells / immunology*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Il17a protein, mouse
  • Il2rb protein, mouse
  • Interleukin-15
  • Interleukin-17
  • Interleukin-2 Receptor beta Subunit