2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Induces Fas-dependent Activation-Induced Cell Death in Superantigen-Primed T Cells

Arch Toxicol. 2002 Oct;76(10):570-80. doi: 10.1007/s00204-002-0390-2. Epub 2002 Aug 6.

Abstract

Immune response against a foreign antigen is characterized by a growth phase, in which antigen-specific T cells clonally expand, followed by a decline phase in which the activated T cells undergo apoptosis, a process termed activation-induced cell death (AICD). In the current study, we have investigated the phase at which 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) acts to downregulate the antigen-specific T cell response. To this end, C57BL/6 +/+ mice were injected with staphylococcal enterotoxin A (SEA) into the footpads (10 micro g/footpad), and simultaneously treated with TCDD (10 or 50 micro g/kg intraperitoneally). At various time points, the draining lymph node (LN) cells were analyzed for SEA-activated T cells. The data demonstrated that in C57BL/6 +/+ mice, TCDD treatment did not alter the growth phase but facilitated the decline phase of SEA-reactive T cells. TCDD caused a significant decrease in the percentage and absolute numbers of CD4(+) and CD8(+) SEA-responsive T cells expressing Vbeta3(+) and Vbeta11(+) but did not affect SEA-nonresponsive Vbeta8(+) T cells. Upon in vitro culture, TCDD-exposed SEA-immunized LN cells exhibited increased levels of apoptosis when compared with the vehicle controls. When Fas-deficient (C57BL/6 lpr/lpr) or Fas ligand defective (C57BL/6 gld/gld) mice were treated with TCDD, they failed to exhibit a decrease in percentage and cellularity of SEA-reactive T cells, thereby suggesting a role of Fas-Fas ligand interactions in the TCDD-induced downregulation of SEA-reactive T cell response. The resistance to TCDD-induced decrease in T cell responsiveness to SEA seen in Fas- and FasL-mutant mice was neither due to decreased aryl hydrocabon receptor (AhR) expression nor to altered T cell responsiveness to SEA. The current study demonstrates that TCDD does not prevent T cell activation, but prematurely induces Fas-based AICD, which may contribute to the deletion of antigen-primed T cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Down-Regulation
  • Enterotoxins / pharmacology*
  • Environmental Pollutants / toxicity*
  • Female
  • Interferon Inducers / immunology
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Polychlorinated Dibenzodioxins / toxicity*
  • Staphylococcus aureus / immunology
  • Superantigens / pharmacology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology*
  • fas Receptor / metabolism*

Substances

  • Enterotoxins
  • Environmental Pollutants
  • Interferon Inducers
  • Polychlorinated Dibenzodioxins
  • Superantigens
  • fas Receptor
  • enterotoxin A, Staphylococcal