Timing and casting for actors of thymic negative selection

We have recently proposed a new model for the differentiation pathway of al pha beta TCR thymocytes, with the CD4 and CD8 coreceptors undergoing an une xpectedly complex series of expression changes. Taking into account this ne w insight, we reinvestigated the timing of thymic negative selection, We fo und that, although endogenous superantigen driven thymic negative selection could occur at different steps during double-positive/single-positive cell transition, this event was never observed among CD4(low)CD8(low) TCRint CD 69(+) thymocytes, i.e., within the first subset to be generated upon TCR-me diated activation of immature double-positive cells. We confirm a role for CD40/CD40L interaction, and the absence of involvement of CD28 costimulatio n, in thymic deletion in vivo. Surprisingly, we found that thymic negative selection was impaired in the absence of Fas, but not Fast, molecule expres sion, Finally, we show involvement in opposing directions for p59(fyn) and SHP-1 molecules in signaling for thymic negative selection.