Journal Article

Nitric oxide and glucocorticoids synergize in inducing apoptosis of CD4<sup>+</sup>8<sup>+</sup> thymocytes: implications for ‘Death by Neglect’ and T-cell function

Orly Cohen, Eliran Ish-Shalom, Shlomit Kfir-Erenfeld, Ingrid Herr and Eitan Yefenof

in International Immunology Meeting Abstracts

Published on behalf of Japanese Society for Immunology

Volume 24, issue 12, pages 783-791
Published in print December 2012 |
Published online September 2012 | | DOI: http://dx.doi.org/10.1093/intimm/dxs083

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Thymic epithelial cells (TECs) play a central role in T-cell development by presenting self-antigens on MHC proteins. Double-positive (DP) thymocytes that fail to interact with TEC via their TCR die by ‘Death by Neglect’. We demonstrated a role for TEC-derived glucocorticoids (GCs) in this process. In a previous study, we used an in vitro system recapitulating Death by Neglect, to demonstrate the involvement of nitric oxide (NO) and inducible NO synthase (iNOS) in this process. In this study, we show that NO synergizes with GCs to induce apoptosis of DP thymocytes in a fetal thymic organ culture. Also, DP thymocytes from iNOS−/− mice are less sensitive to GC-induced apoptosis. Furthermore, the number of DP thymocytes in iNOS−/− mice is higher than in wild-type mice, suggesting a role for NO in Death by Neglect. This phenomenon effects T-cell function profoundly: iNOS−/− T cells do not respond to TCR-mediated activation signals, measured by up-regulation of CD69, IL-2R and IFNγ secretion. This failure to activate is a result of TCR incompetence because iNOS−/− T cells respond to TCR-independent stimuli (phorbol myristate acetate and calcium ionophore). This study suggests that NO and GCs synergize to execute TEC-induced death of DP thymocytes.

Keywords: Death by Neglect; glucocorticoids; inducible nitric oxide synthase; nitric oxide; thymocytes; T-cell activation; synergy

Journal Article.  5388 words.  Illustrated.

Subjects: Immunology ; Biochemical Immunology

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