Prevention of injury-induced suppression of T-cell immunity by the CD1d/NKT cell-specific ligand alpha-galactosylceramide

Shock. 2008 Feb;29(2):269-77. doi: 10.1097/shk.0b013e31811ff60c.

Abstract

Infection, sepsis, and multiple organ failure continue to be significant factors leading to morbidity and mortality after severe injury. Studies by our laboratory and others have identified injury-induced defects in both innate and adaptive components of host defense. We previously reported that CD1d-restricted natural killer T (NKT) cells actively suppress effector T-cell immunity after burn injury via production of excess IL-4 and failure to produce IFN-gamma. alpha-Galactosylceramide (alpha-GalCer) is a synthetic NKT cell-specific ligand presented exclusively to invariant NKT cells and is known to improve immunity against tumors and infection by promoting IFN-gamma production. Here, we confirmed the role of Valpha14-Jalpha281 invariant NKT cells in mouse model of burn injury-induced suppression of T-cell immunity and further asked whether alpha-GalCer can improve immunity after injury via similar mechanisms. We observed that systemic treatment with alpha-GalCer prevented the injury-induced suppression of Ag-specific T-cell responsiveness both in vitro and in vivo and restored the ability of splenic lymphocytes to produce both IL-2 and IFN-gamma. Moreover, burn injury was associated with diminished expression of major histocompatibility complex II and CD40 on antigen presenting cells that were both restored by alpha-GalCer treatment to levels seen in sham-treated mice. Collectively, these data suggest that, via manipulation of the NKT cell population, we may be able to maintain T-cell function and improve host defense after burn injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1 / metabolism*
  • Antigens, CD1d
  • Burns / physiopathology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD40 Antigens / metabolism
  • Cell Proliferation / drug effects
  • Flow Cytometry
  • Galactosylceramides / pharmacology*
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism
  • Interleukin-4 / metabolism
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism

Substances

  • Antigens, CD1
  • Antigens, CD1d
  • CD40 Antigens
  • Galactosylceramides
  • Interleukin-2
  • alpha-galactosylceramide
  • Interleukin-4
  • Interferon-gamma