Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) renders influenza virus-specific CD8+ T cells hyporesponsive to antigen.
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 (IFNgamma) production by these cells. The observation that neither proliferation nor IFNgamma 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.
Graduate Program in Pharmacology, Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington 99164, USA.
Kristen A
KA
Mitchell
B Paige
BP
Lawrence
D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016827:CD8 Antigens / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005434:Flow Cytometry; D005805:Genes, MHC Class I / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008198:Lymph Nodes / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000276:immunology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D013268:Stimulation, Chemical; D014758:Viral Core Proteins / Q000276:immunology
D000956:Antigens, Viral; D016827:CD8 Antigens; D004785:Environmental Pollutants; D010446:Peptide Fragments; D000072317:Polychlorinated Dibenzodioxins; D014758:Viral Core Proteins; C102366:nucleoprotein (366-374), influenza virus; D007371:Interferon-gamma