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International Immunology Advance Access originally published online on August 19, 2009
International Immunology 2009 21(10):1113-1123; doi:10.1093/intimm/dxp079
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© The Japanese Society for Immunology. 2009. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Nitric oxide cooperates with glucocorticoids in thymic epithelial cell-mediated apoptosis of double positive thymocytes

Orly Cohen, Shlomit Kfir-Erenfeld, Rachel Spokoini, Yael Zilberman, Eitan Yefenof and Ronit Vogt Sionov

Department of Immunology, The Lautenberg Center for General and Tumor Immunology, Institute of Medical Research, The Hebrew University–Hadassah Medical School, PO Box 12272, Jerusalem 91120, Israel

Correspondence to: E. Yefenof; E-mail: eitany{at}ekmd.huji.ac.il

T cell development in the thymus is controlled by thymic epithelial cells (TE). While it is accepted that TE interact with maturing T cells, the mechanisms by which they trigger ‘death by neglect’ of double-positive (DP) thymocytes are poorly understood. We and others have demonstrated a role for TE-derived glucocorticoids (GCs) in this process. We have studied TE-induced apoptosis using an in vitro system based on co-culturing a thymic epithelial cell line (TEC) with DP thymic lymphoma cells or thymocytes (DP thymic cells). Here, we demonstrate that nitric oxide (NO·) is also involved in this death process. The inducible nitric oxide synthase (iNOS) inhibitors NG-methyl-L-arginine and 1,4-PBIT attenuated TEC-induced apoptosis of DP thymic cells. Co-cultivation of TEC with DP thymic cells increased the expression of iNOS in TEC. A concomitant increase in NO· was detected by staining with DAF-FM diacetate. Moreover, the iNOS-regulating cytokines IL-1{alpha}, IL-1β and IFN{gamma} were up-regulated upon interaction of TEC with DP thymic cells. Neutralizing IL-1R or IFN{gamma} reduced TEC-induced apoptosis of DP thymic cells. Cardinally, NO· synergizes with GCs in eliciting apoptosis of DP thymic cells. Our data indicate that a cross-talk between DP thymic cells and TEC is required for proper induction of iNOS-up-regulating cytokines with a subsequent increase in iNOS expression and NO· production in TEC. NO·, in turn, cooperates with GCs in promoting death by neglect. We suggest that NO· together with GCs fine-tune the T cell selection process.

Keywords: cytokines, death by neglect, inducible nitric oxide synthase, maturing T cells, synergy

Transmitting editor: R. Medzhitov

Received 7 December 2008, accepted 17 July 2009.


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