Cellular and genetic basis for suppression of cytotoxic T cell generation by haloaromatic hydrocarbons
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abstract
Generation of allospecific cytotoxic T cells in C57Bl/6 mice is significantly impaired following exposure to TCDD at doses as low as 4 ng/kg. T helper activity, as assessed by the ability to produce Interleukin 2, and frequency of CTL precursors appear unaffected in treated animals and thus the TCDD-induced suppressor cells we have described are primarily responsible for the reduction in the CTL response. Suppression of CTL generation in DBA/2 mice requires a 10--100-fold greater dose than in C57Bl/6, consistent with the observation that the Ah locus gene(s) of DBA/2 mice code for TCDD receptors with low binding affinity for TCDD. Other haloaromatic hydrocarbons (3,3'4,4'-tetrachlorobiphenyl and Aroclor 1254), capable of binding to the TCDD receptor, also suppress CTL generation, whereas the 2,2',4,4',6,6'-hexachlorobiphenyl molecule that lacks affinity for the TCDD receptor does not suppress CTL. The immunotoxic effects of TCDD in C57B/6 and DBA/2 mice occur at dose levels below those required to induce mixed-function oxidase enzymes in the liver. Suppression of CTL by TCDD is associated with increased susceptibility to lethal herpes virus type II infection. These data suggest that low levels of TCDD may interact with cytoplasmic receptors for TCDD in the thymus and induce biologically significant immunosuppression through activation of suppressor cells.
