Early consequences of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on the activation and survival of antigen-specific T cells.
TCDD is a potent immunotoxicant that suppresses adaptive immunity by mechanisms that are not well defined. To gain insight at the level of the T cell, we used the DO11.10 transgenic T-cell receptor (TCR) mouse model in an adoptive transfer approach to characterize the influence of TCDD on the responsiveness of antigen-specific CD4+ T cells in vivo. Flow cytometry was used to track the response of the OVA-specific transgenic CD4+ T cells in syngeneic recipients using an antibody specific for the transgenic TCR (KJ1-26 [KJ]). Consistent with a previous report, exposure of the recipient mice to TCDD (15 microg/kg po) did not alter the initial expansion of the CD4+KJ+ T cells in the spleen following immunization with OVA but resulted in a significant decline in the number of cells present on and after day 4. The degree of decline was dependent on the dose of TCDD. On day 3 after OVA injection, a higher percentage of the CD4+KJ+ T cells in the spleens of TCDD-treated mice had down-regulated the expression of CD62L, a phenotype associated with T-cell activation. Also on day 3, an increased number of CD4+KJ+ T cells were found in the blood of TCDD-treated mice. However, as in the spleen, the number of CD4+KJ+ T cells in the blood rapidly declined on day 4. CD4+KJ+ T cells in both the spleen and blood of TCDD-treated mice failed to up-regulate CD11a, an adhesion molecule important for sustained interaction between T cells and DC whereas the up-regulation of the adhesion molecule CD49d was not altered. Based on analysis of cell division history, CD4+KJ+ T cells in vehicle-treated mice continued to divide through day 4 whereas CD4+KJ+ T cells in TCDD-treated mice showed no further division after day 3. Increased annexin V staining on CD4+KJ+ T cells in TCDD-treated mice was also observed but not until days 5 and 6. Fas-deficient CD4+KJ+ T cells were depleted from the spleen of TCDD-treated mice in a manner similar to wild-type CD4+KJ+ T cells, suggesting that Fas signaling does not play a critical role in this model. On the other hand, gene array analysis of purified CD4+KJ+ T cells on day 3 showed that the expression of several genes associated with cell survival/death were altered by TCDD. Taken together, the results are consistent with our hypothesis that TCDD provides an early but inappropriate activation signal to the antigen-specific T cells that allows, and possibly enhances, the initial activation and proliferation of the T cells, yet at the same time, interferes with the vital expression of certain adhesion/costimulatory molecules that serve to enhance the survival of the T cells. These changes result in truncated proliferation, increased T-cell death, and suppression of the adaptive immune response.
Funatake
Castle J
CJ
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA.
Dearstyne
Erica A
EA
Steppan
Linda B
LB
Shepherd
David M
DM
Spanjaard
Elena S
ES
Marshak-Rothstein
Ann
A
Kerkvliet
Nancy I
NI
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D040881:CD11a Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D019041:L-Selectin / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D023421:Models, Animal; D010047:Ovalbumin / Q000276:immunology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
D040881:CD11a Antigen; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D019041:L-Selectin; D010047:Ovalbumin