CD30 mediates thymic Programmed Cell Death (PCD) through a BCL-2 sensitive pathway

The CD30 molecule is a TNF-R member, whose function in normal and neoplastic lymphocytes is still largely unknown. To study the role of CD30 on T cells, transgenic mice were generated using the complete open reading frame of murine CD30 (1.6 kb) under the transcriptional control of the minimal murine CD4 promoter (487 bp), containing the transcription initiation site and 70 bp of the untranslated first exon, and the minimal CD4 enhancer (339 bp). Multiple lines of mice were obtained in which high surface CD30 expression was restricted to T cells in all different stages of differentiation. The mice had normal thymic maturation, but a decreased number of peripheral T cells in secondary lymphoid organs. The CD30 overexpression did not alter the thymocyte PCD, induced by radiation, dexamethasone, ionomycin, PMA and activation via Fas or CD3, but it allowed PCD with CD30 cross-linking by anti-CD30 or CD30L. It also enhanced PCD induced via CD3 + CD30 co-stimulation. CD30 induced PCD was blocked by caspase 1 and caspase 3 inhibitors (Z-YVAD-cmk and Z-DEVD-fmk). CD30 induced PCD did not influence NFκB protein or Fas, Flice, Fadd, Flip, Tradd, Traf-1 and 2 mRNA levels. However, anti-CD30 induced PCD was totally blocked by simultaneous BCL-2 overexpression. These results demonstrate that CD30 is an important effector of thymic PCD.