A requirement for IL-2/IL-2 receptor signaling in intrathymic negative selection

The Journal of Immunology : Official Journal of the American Association of Immunologists
H Bassiri, S R Carding

Abstract

The nature of the signals that influence thymocyte selection and determine the fate of CD4(+)8(+) (double positive) thymocytes remains unclear. Cytokines produced locally in the thymus may modulate signals delivered by TCR-MHC/peptide interactions and thereby influence the fate of double-positive thymocytes. Because the IL-2/IL-2R signaling pathway has been implicated in thymocyte and peripheral T cell survival, we investigated the possibility that IL-2/IL-2R interactions contribute to the deletion of self-reactive, Ag-specific thymocytes. By using nontransgenic and transgenic IL-2-sufficient and -deficient animal model systems, we have shown that during TCR-mediated thymocyte apoptosis, IL-2 protein is expressed in situ in the thymus, and apoptotic thymocytes up-regulate expression of IL-2RS: IL-2R(+) double-positive and CD4 single-positive thymocytes undergoing activation-induced cell death bind and internalize IL-2. IL-2-deficient thymocytes are resistant to TCR/CD3-mediated apoptotic death, which is overcome by providing exogenous IL-2 to IL-2(-/-) mice. Furthermore, disruption or blockade of IL-2/IL-2R interactions in vivo during Ag-mediated selection rescues some MHC class II-restricted thymocytes from apoptosis. Collecti...Continue Reading

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Citations

Jul 3, 2004·Nature Reviews. Drug Discovery·John J O'SheaPaul S Changelian
Feb 9, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Janos NacsaGenoveffa Franchini
Apr 5, 2005·Immunology·Nadzieja DrelaEwa Kozłowska
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