Journal Article

Exposure to 2,3,7,8-Tetrachlorodibenzo-<i>p</i>-dioxin (TCDD) Renders Influenza Virus-Specific CD8<sup>+</sup> T Cells Hyporesponsive to Antigen

Kristen A. Mitchell and B. Paige Lawrence

in Toxicological Sciences

Volume 74, issue 1, pages 74-84
Published in print July 2003 | ISSN: 1096-6080
Published online July 2003 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfg110
Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Renders Influenza Virus-Specific CD8+ T Cells Hyporesponsive to Antigen

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While considerable evidence indicates that exposure to the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impairs T cell function, the precise mechanism underlying this effect is not well understood. Furthermore, relatively little is known about the effects of TCDD on the fate of activated, antigen-specific T cells in vivo. In the present study, we took advantage of major histocompatibility complex (MHC) class I-restricted tetramers and clonotypic anti-T cell receptor (TCR) antibodies to follow the fate of influenza virus-specific CD8+ T cells in mice treated with TCDD. Exposure to TCDD suppressed the clonal expansion of influenza virus-specific CD8+ T cells, resulting in a three- to five-fold reduction in the number of cytotoxic T lymphocytes (CTL) in the lymph node, as compared to vehicle-treated mice. Studies to address possible mechanisms for the diminished CTL response failed to show evidence for increased apoptosis in virus-specific CD8+ T cells from TCDD-exposed mice. However, treatment with TCDD reduced the number of proliferating virus-specific CD8+ T cells by as much as 70% on day 7 post infection. Moreover, ex vivo restimulation of lymph node cells with influenza virus nucleoprotein (NP366–374) peptide and exogenous interleukin-2 (IL-2) only partially restored the proliferation of influenza virus-specific CD8+ T cells from TCDD-exposed mice and failed to stimulate interferon-gamma (IFNγ) production by these cells. The observation that neither proliferation nor IFNγ production by CD8+ T cells could be completely restored, even when cells were provided with optimal stimulation, suggests that exposure to TCDD drives antigen-specific CD8+ T cells into a state of unresponsiveness similar to anergy.

Keywords: TCDD (dioxin); immunosuppression; CD8+ T lymphocytes; antigen-specific; tetramer, influenza virus; anergy; mouse; lymph node; in vivo

Journal Article.  8755 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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