Caspases

U ncontrolled lymphoproliferation is a characteristic feature of lymphomas and leukemias. Nonmalignant lym-phoproliferative diseases are also observed in humans as well as in lpr (lymphoproliferation) and gld (generalized lymphad-enopathy) mice. The discoveries that spontaneous mutations of Fas (APO-1/CD95) or its ligand (FasL) were associated with the lpr and gld phenotypes led to a satisfying explanation as to how deficiency of a pivotal lymphocyte apoptotic pathway (Fas–FasL) caused accumulation of activated lym-phocytes in the peripheral immune system (1). A second important consequence of the failure to delete activated cells of the immune system is systemic autoimmunity—which can be explained by the persistence of potentially self-reac-tive T cells and, most likely, antigen-presenting cells in the peripheral immune system (2). The remarkable strides made in defining the cellular biochemistry of apoptosis over the last 5 years have led to several predictions of protein function that, most definitively, could be tested by gene targeting in mice. Early predictions were that deletion of components of the Fas signal trans-duction pathway would lead to a phenotype similar to lpr. Deletions of Fas-associated death domain (FADD) or caspase-8 were lethal in the embryo due to impaired cardiac development, and were therefore uninformative regarding mature T cell function (3, 4). However, FADD-deficient T cells in recombination activating gene (RAG)-1 Ϫ / Ϫ mice or transgenic mice expressing a dominant negative FADD protein were completely resistant to Fas-mediated apoptosis, as expected, but demonstrated reduced T cell proliferation rather than lymphoproliferation and autoimmunity (5, 6). The results of the studies by Alam et al. (7) and Kennedy et al. (8) in this issue provide a potential explanation for the contrasting effects of Fas versus FADD deficiency. Both studies report that, in addition to the well-defined role of upstream caspases in initiating the proteolytic cascade required for the inactivation and packaging of cellular constituents in apoptosis, caspases are necessary for proliferation of primary human T cells in vitro. This conclusion was based on two major observations: (a) T cell proliferation was inhibited by cell-permeable caspase inhibitors, and (b) caspases were cleaved within hours after CD3 engagement. Although these data are compelling, some caveats should be noted. Most commercially available irreversible caspase inhibitors are not absolutely specific for any individual caspase, so that precise intracellular targets cannot be certain (9). Could these inhibitors be exerting a " toxic " effect on primary T cells, thus accounting for their lack of prolifera-tion? Alam …