CD30 overexpression enhances negative selection in the thymus and mediatesprogrammed cell death via a Bcl-2-sensitive pathway

The biological function of CD30 in the thymus has been only partially eluci dated, although recent data indicate that it may be involved in negative se lection. Because CD30 is expressed only by a small subpopulation of medulla ry thymocytes, we generated transgenic (Tg) mice overexpressing CD30 in T l ymphocytes to further address its role in T cell development. CD30 Tg mice have normal thymic size with a normal number and subset distribution of thy mocytes. In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg m ice have normal survival and responses to apoptotic stimuli such as radiati on, dexamethasone, and Fas. However, in contrast to controls, CD30 Tg thymo cytes are induced to undergo programmed cell death (PCD) upon cross-linking of CD30, and the simultaneous engagement of TCR and CD30 results in a syne rgistic increase in thymic PCD. CD30-mediated PCD requires caspase 1 and ca spase 3, is not associated with the activation of NF-KB or c-Jun, but is to tally prevented by Bcl-2, Furthermore, CD30 overexpression enhances the del etion of CD4(+)/CD8(+) thymocytes induced by staphylococcal enterotoxin B s uperantigen and specific peptide. These findings suggest that CD30 may act as a costimulatory molecule in thymic negative selection.