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

The nature of the signals that influence thymocyte selection and determine the fate of CD4(+)8(+) (double positive) thymocytes remains unclear. Cytoki nes produced locally in the thymus may modulate signals delivered by TCR-MH C/peptide interactions and thereby influence the fate of double-positive th ymocytes. Because the IL-2/IL-2R signaling pathway has been implicated in t hymocyte and peripheral T cell survival, we investigated the possibility th at 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-posi tive 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. Collectively, these findings provide evidence for the direct involvement of the IL-2/IL-2R signaling pathway in the deletion of Ag-specific thymocyte populations and suggest that CD4 T c ell hyperplasia and autoimmunity in IL-2-/- mice is a consequence of ineffe ctive deletion of self-reactive T cells.