Title: Early consequences of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on the activation and survival of antigen-specific T cells.

Authors: Funatake, Castle J; Dearstyne, Erica A; Steppan, Linda B; Shepherd, David M; Spanjaard, Elena S; Marshak-Rothstein, Ann; Kerkvliet, Nancy I

Published In Toxicol Sci, (2004 Nov)

Abstract: 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.

PubMed ID: 15310856

MeSH Terms: Adoptive Transfer; Animals; Apoptosis/drug effects; CD11a Antigen/metabolism; CD4-Positive T-Lymphocytes/drug effects*; CD4-Positive T-Lymphocytes/immunology; CD4-Positive T-Lymphocytes/pathology; Cell Survival/drug effects; Dose-Response Relationship, Drug; Environmental Pollutants/toxicity*; Female; L-Selectin/metabolism; Lymphocyte Activation/drug effects*; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Models, Animal; Ovalbumin/immunology; Polychlorinated Dibenzodioxins/toxicity*; Spleen/immunology; Spleen/metabolism; Up-Regulation