Suppression of murine cytotoxic T-lymphocyte induction following exposure to 7,12-dimethylbenz[A]anthracene: dysfunction of antigen recognition.
Exposure of murine lymphocytes to the carcinogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) results in significant suppression of a variety of immunological parameters, including the induction of cytotoxic T-lymphocytes (CTL). This CTL suppression may be reversed in vitro by the addition of exogenous cellular activation products, including IL-2. The current study demonstrated that DMBA-induced CTL suppression occurs throughout the induction process, with the most pronounced effect occurring within 24-48 h of initiation. IL-2-mediated restoration of suppression is effective only within this critical window. These findings suggest an effect by DMBA on both the T-helper (Th) and CTL-precursor (CTLp) subsets. Alloantigen-specific CTL generated from murine thymocytes in the presence of DMBA and Th-derived factors (thus circumventing the Th) displayed an almost identical degree of CTL suppression to that of splenocytes, indicating a direct effect of DMBA on the CTLp. Antigen nonspecific, polyclonal CTL activation by the lectin leucoagglutinin or by IL-2 (LAK cells) was unaffected by chemical exposure, indicating that DMBA preferentially affects antigen-specific activation rather than the cytolytic process itself. Conversely, polyclonal CTL induced with monoclonal antibodies directed against the T-cell receptor-associated subunit CD3, in the presence of conditioned medium, was suppressed in a manner similar to antigen-mediated CTL. The CD3 receptor subunit acts as a transmembrane activation signal following binding of antigen to the specific receptor, further implicating dysfunction of antigen recognition or signal processing following DMBA exposure. This was confirmed by the observation that DMBA exposure prevents the anamnestic response of CTL memory cells following re-exposure to eliciting tumor antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
House
R V
RV
Department of Cellular and Molecular Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Pallardy
M J
MJ
Dean
J H
JH
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D005260:Female; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010835:Phytohemagglutinins / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
D007376:Interleukin-2; D010835:Phytohemagglutinins; D011948:Receptors, Antigen, T-Cell; C100156:leukoagglutinins, plants; D015127:9,10-Dimethyl-1,2-benzanthracene