Caspases, a family of cysteine proteases, are critical mediators of apoptos
is, To address the importance of caspases in thymocyte development, we have
generated transgenic:mice that express the baculovirus protein p35, a vira
l caspase inhibitor, specifically in the thymus, p35 expression inhibited F
as (CD95)-, CD3-, or peptide-induced caspase activity in vitro and conferre
d resistance to Fas-induced apoptosis, However, p35 did not block specific
peptide-induced negative selection in OT1 and HY TCR transgenic mouse model
s, Even the potent pharmacological caspase inhibitor zVAD-FMK (benzyloxycar
bonyl-Val-Ala-Asp-fluoromethyl-ketone) could not prevent peptide-induced de
letion of OT1 thymocytes, although it improved basal thymocyte survival in
vitro. Moreover, the developmental block observed in rag1(-/-) thymocytes,
which lack pre-TCR signaling, was also not rescued by p35 expression. These
results indicate that caspase-independent signal transduction pathways can
mediate thymocyte death during normal T cell development.