Inhibition of TC-1 cytokine production, effector cytotoxic T lymphocyte development and alloantibody production by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant and prototypic ligand for the aryl hydrocarbon receptor, is a potent immunotoxicant. To understand the underlying mechanisms of TCDD immunotoxicity, we have characterized the time course of changes in CTL, alloantibody, and cytokine responses to the P815 tumor allograft in C57B1/6 mice treated with 0 or 15 microg TCDD/kg. Suppression of CTL activity by TCDD directly correlated with reduced numbers of splenic CTL effector cells identified by their CD8+CD44 high CD45RB low phenotype, while suppression of the alloantibody response correlated with a lack of expansion of the B220+ splenocyte population. Cytokine production was differentially modulated following TCDD treatment. Although type 1 cytokine production (IFN-gamma, IL-2, and TNF) was initially induced in TCDD-treated mice, production failed to increase normally after day 5. In contrast, the production of IL-1 beta, IL-4, and IL-6 was mostly unaffected by TCDD exposure. This differential effect of TCDD on cytokine production was reflected in the degree of suppression of specific alloantibody isotypes. TCDD abrogated the production of IgG2a (promoted by IFN-gamma), but had much less effect on the level of IgG1 (promoted by IL-4). IgM Ab titers were also highly suppressed. CD8+ cells were the exclusive producers of IFN-gamma and IL-2 when spleen cells from P815-injected mice were cultured in vitro on days 4 to 7 after P815 injection. However, CD4+ cells were shown to play a crucial role in the generation of both CTL and alloantibody responses, since their depletion in vivo abolished both responses. Based on similar temporal effects produced by TCDD and anti-CD4 Ab on alloimmune responses, we postulate that TCDD interferes with the initial activation of CD4+ T cells, which leads to downstream inhibition of the activation and/or differentiation of CD8+ T cells and B cells. In addition, since delayed treatment with either anti-CD4 Ab or TCDD suppressed the alloantibody but not the CTL response, TCDD may also affect later CD4+ T helper-B cell interactions.
Kerkvliet
N I
NI
Department of Agricultural Chemistry, Environmental Health Sciences Center, Oregon State University, Corvallis 97331, USA.
Baecher-Steppan
L
L
Shepherd
D M
DM
Oughton
J A
JA
Vorderstrasse
B A
BA
DeKrey
G K
GK
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000961:Antilymphocyte Serum / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D007132:Immunoglobulin Isotypes / Q000187:drug effects / Q000276:immunology; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D007518:Isoantibodies / Q000096:biosynthesis* / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count / Q000187:drug effects; D008212:Lymphocyte Depletion; D008297:Male; D012515:Mast-Cell Sarcoma; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics
D000961:Antilymphocyte Serum; D016207:Cytokines; D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007518:Isoantibodies; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma