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Misra, Ravi S.

Cell and Molecular Biology Program

2006

Ph. D.

The innate arm of the immune system is responsible for early elimination of many pathogens encountered by the body. However, if the innate immune system cannot, activation of the adaptive arm of the immune system occurs, generating activated effector immune cells. This leads to clonal expansion of immune cells with specific antigen receptors. Following clearance of the pathogen, many responding cells undergo apoptosis. Apoptosis is induced via Death Receptors or growth factor withdrawal, which activates a family of cysteine proteases known as caspases, and leads to the subsequent cleavage of hundreds of substrates. Caspases are best known for their role in apoptosis, and their activation occurs mainly by proteolytic processing. However, emerging evidence supports a role for them in non-apoptotic processes. For example, caspase-mediated cleavage of pro-Interleukin-1 leads to its maturation and secretion. Following injury, neuron and hepatocyte regeneration is enhanced by activation of the Death Receptor Fas. T cell activation using suboptimal stimulation and fibroblast proliferation can be augmented by Fas engagement. Conversely, blockade of caspase activation inhibits T cell activation. Thus, activation of caspases is linked to activation of T cells. c-FLIP (FLICE-like inhibitory protein) is a Death Receptor inhibitor. The long variant of c-FLIP (c-FLIP[subscript L]) can activate full-length caspase-8. A 43kD fiagrnent of c- FLIP[subscript L] (p43FLIP) is generated through proteolysis by active caspase-8. p43FLIP interacts with the NF-[kappa]B signaling proteins, TNF Receptor Associated Factor (TRAF)2 and Receptor Interacting Protein (RIP)1. Thus, c-FLIP[subscript L] may link caspase activation with NF-[kappa]B signals during T cell activation.