Incompetent Killers

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Science  05 Dec 2003:
Vol. 302, Issue 5651, pp. 1629
DOI: 10.1126/science.302.5651.1629a

In the immune system, cytotoxic T cells (CTLs) destroy target cells by binding to them and fusing the contents of cytolytic granules—a specialized form of secretory lysosome—with the target cell membrane, causing cell lysis and death. The cell-cell contact site is known as the immunological synapse. Clark et al. examined CTLs from patients with Hermansky Pudlak syndrome—a rare autosomal recessive disease linked to platelet defects and albinism. They discovered that the CTLs from these patients lacked a protein complex known as AP3—previously implicated in membrane trafficking to the lysosome. The patients' CTLs could bind to target cells but could not appropriately polarize and transport their lytic granules to the immunological synapse. Feldmann et al. studied CTLs from a subset of patients with a different disorder: familial hemophagocytic lymphohistiocytosis. In this case, CTLs formed normal-looking immunological synapses with target cells, complete with focused lytic granules, but the granules failed to fuse because of the absence of functional Munc13-4—a protein involved in vesicle priming. Both studies highlight how CTLs modify existing membrane trafficking mechanisms to perform specialized cellular functions. — SMH

Nature Immunol. 4, 1111 (2003); Cell 115, 461 (2003).

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