How caspase-8 activity is regulated in the RNA viral-sensing pathway is not entirely clear. Since caspase-8 is also critical for the activation and survival of T cells as well as other cell types, the regulation between death and growth processes is extremely important to T cell function and homeostasis. A critical regulator of caspase-8 activation is the caspase-8 paralogue, c-FLIP. Originally identified in certain DNA viruses, the cellular homolog was described a year later. c-FLIP is expressed in three forms, full-length cFLIP-Long, and two alternatively spliced forms that are upregulated following T cell activation, c-FLIP-Short and c-FLIP-Reduced. Since all three forms of cFLIP, as well as v-FLIP, inhibit death receptor-induced activation of caspase-8 and cell death, it has been less clear what is the distinction, if any, among these various forms of c-FLIP. A clue to the explanation came when it was determined that c-FLIPL can heterodimerize with caspase-8, independently of death receptor ligation, via their mutual Death Effector Domains. In this complex, c-FLIPL contains within its enzymatically inert Cterminus an activation loop for caspase-8. However, this loop is absent in c-FLIPS, c-FLIPR, and v-FLIP, even though they can also heterodimerize with caspase-8 by their N-terminal DED. Thus, c-FLIPL emerges as an activator of caspase-8 during the initiation of cell growth of T cells, whereas the later upregulation of c-FLIPS, or the presence of v-FLIPs, would be Cyclizine dihydrochloride predicted to promote reduced activation of caspase-8 and perhaps serve to terminate T cell growth or function. This model is consistent with our observations that increased expression of c-FLIPL in T cells resulted in their hyperproliferation, augmented production of certain cytokines, and ability to protect mice from CVB3 infection, whereas increased expression of c-FLIPS resulted in reduced activation of caspase-8 and NF-kB, as well as reduced T cell survival following antigen activation. We thus examined the role of c-FLIPS during infection with CVB3 and observed that, in contrast to mice expressing c-FLIPL in the T cell compartment, c-FLIPS-transgenic mice were more susceptible to CVB3 infection, particularly female mice that are usually resistant. In vitro mechanistic studies using CVB3 infection of mouse embryonic fibroblasts further revealed that cFLIPL Fosaprepitant dimeglumine salt promoted caspase-8 activation and interferon production, whereas c-FLIPS and v-FLIPs did the opposite.