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Title: Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery

Abstract

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effects of DES on T-cell differentiation in the thymus using the HY-TCR transgenic (Tg) mouse model in which the female mice exhibit positive selection of T cells bearing the Tg TCR, while the male mice show negative selection of such T cells. In female HY-TCR-Tg mice, exposure to DES showed more pronounced decrease in thymic cellularity when compared to male mice. Additionally, female mice also showed a significant decrease in the proportion of double-positive (DP) T cells in the thymus and HY-TCR-specific CD8{sup +} T cells in the periphery. Male mice exhibiting negative selection also showed decreased thymic cellularity following DES exposure. Moreover, the male mice showed increased proportion of double-negative (DN) T cells in the thymus and decreased proportion of CD8{sup +} T cells. The density of expression of HY-TCR on CD8{sup +} cells was increased following DES exposure in both females and males. Finally, the proliferative response of thymocytes to mitogens and peripheral lymph node T cells to male H-Y antigen was significantly altered in female and male mice following DESmore » treatment. Taken together, these data suggest that DES alters T-cell differentiation in the thymus by interfering with positive and negative selection processes, which in turn modulates the T-cell repertoire in the periphery.« less

Authors:
 [1];  [1];  [2]
  1. Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 (United States)
  2. Department of Pharmacology and Toxicology, PO Box 980613, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0613 (United States). E-mail: pnagark@hsc.vcu.edu
Publication Date:
OSTI Identifier:
20783459
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 212; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2005.07.012; PII: S0041-008X(05)00424-2; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIGENS; APOPTOSIS; CELL DIFFERENTIATION; DISEASES; LYMPH NODES; MICE; MITOGENS; PRENATAL EXPOSURE; THYMOCYTES; THYMUS; TOXICITY

Citation Formats

Brown, Nicole, Nagarkatti, Mitzi, and Nagarkatti, Prakash S. Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery. United States: N. p., 2006. Web. doi:10.1016/j.taap.2005.07.012.
Brown, Nicole, Nagarkatti, Mitzi, & Nagarkatti, Prakash S. Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery. United States. doi:10.1016/j.taap.2005.07.012.
Brown, Nicole, Nagarkatti, Mitzi, and Nagarkatti, Prakash S. Sat . "Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery". United States. doi:10.1016/j.taap.2005.07.012.
@article{osti_20783459,
title = {Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery},
author = {Brown, Nicole and Nagarkatti, Mitzi and Nagarkatti, Prakash S.},
abstractNote = {Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effects of DES on T-cell differentiation in the thymus using the HY-TCR transgenic (Tg) mouse model in which the female mice exhibit positive selection of T cells bearing the Tg TCR, while the male mice show negative selection of such T cells. In female HY-TCR-Tg mice, exposure to DES showed more pronounced decrease in thymic cellularity when compared to male mice. Additionally, female mice also showed a significant decrease in the proportion of double-positive (DP) T cells in the thymus and HY-TCR-specific CD8{sup +} T cells in the periphery. Male mice exhibiting negative selection also showed decreased thymic cellularity following DES exposure. Moreover, the male mice showed increased proportion of double-negative (DN) T cells in the thymus and decreased proportion of CD8{sup +} T cells. The density of expression of HY-TCR on CD8{sup +} cells was increased following DES exposure in both females and males. Finally, the proliferative response of thymocytes to mitogens and peripheral lymph node T cells to male H-Y antigen was significantly altered in female and male mice following DES treatment. Taken together, these data suggest that DES alters T-cell differentiation in the thymus by interfering with positive and negative selection processes, which in turn modulates the T-cell repertoire in the periphery.},
doi = {10.1016/j.taap.2005.07.012},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 212,
place = {United States},
year = {Sat Apr 15 00:00:00 EDT 2006},
month = {Sat Apr 15 00:00:00 EDT 2006}
}
  • BALB/c mice treated with total lymphoid irradiation (TLI) develop non-antigen-specific suppressor cells of the adoptive secondary antibody response and of the mixed leukocyte reaction. Suppressors of the adoptive anti-DNP response were eliminated by incubation of spleen cells with anti-Thy-1.2 or anti-thymus-leukemia (TL) antiserum and complement before cell transfer. Thymectomy before TLI prevented the appearance of the latter suppressor cells. On the other hand, suppressors of the MLR were eliminated by incubation of spleen cells with anti-Thy-1.2 but not anti-TL antiserum and complement. Thymectomy before TLI did not prevent their subsequent development. Thus, two subpopulations of suppressor T cells that differmore » in the expression of the TL surface antigen, dependence on the presence of the thymus, and in regulatory functions develop after TLI. The TL+, thymus-dependent cell suppresses the adoptive antibody response, and the TL-, thymus-independent cell suppresses the MLR.« less
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