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An excellent review of synapses formed by T cell, B cells, and NK cells. Detailed description of spatial and, importantly, temporal composition of T cell and NK cell synapses.
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Adhesion molecules, CD11a and CD11b, co-stimulatory CD2, and F-actin accumulate at the pSMAC of the NKIS, whereas perforin polarizes to the cSMAC area. The accumulation of F-actin and other receptors at the pSMAC depends on activity of WASp and actin rearrangements, but is independent of microtubule (MT) polarization. Perforin polarization, however, is dependent on WASp activity and both actin and MT cytoskeleton. Authors demonstrate that the accumulation of the activation receptors and perforin polarization to the IS are sequential processes and the NKIS is formed in distinct steps with actin rearrangements first, followed by MT polarization.
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Orange J.S., Harris K.E., Andzelm M.M., Valter M.M., Geha R.S., and Strominger J.L. The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proc Natl Acad Sci U S A 100 (2003) 14151-14156. Adhesion molecules, CD11a and CD11b, co-stimulatory CD2, and F-actin accumulate at the pSMAC of the NKIS, whereas perforin polarizes to the cSMAC area. The accumulation of F-actin and other receptors at the pSMAC depends on activity of WASp and actin rearrangements, but is independent of microtubule (MT) polarization. Perforin polarization, however, is dependent on WASp activity and both actin and MT cytoskeleton. Authors demonstrate that the accumulation of the activation receptors and perforin polarization to the IS are sequential processes and the NKIS is formed in distinct steps with actin rearrangements first, followed by MT polarization.
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Orange J.S., Ramesh N., Remold-O'Donnell E., Sasahara Y., Koopman L., Byrne M., Bonilla F.A., Rosen F.S., Geha R.S., and Strominger J.L. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci U S A 99 (2002) 11351-11356
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The signaling complexes are assembled at the aNKIS, but are not present at the iNKIS. While formation of the aNKIS requires excessive remodeling of cortical and cytoplasmic cytoskeleton, the iNKIS does not require rearrangements of cytoskeleton or cytoplasmic structures on a large scale. Interestingly, Lck, Itk, PKCθ and ZAP70 are found to partially co-localize with MTOC, indicating that a subset of these proteins interacts with MTOC and may be transported with MTOC to the IS.
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Vyas Y.M., Mehta K.M., Morgan M., Maniar H., Butros L., Jung S., Burkhardt J.K., and Dupont B. Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions. J Immunol 167 (2001) 4358-4367. The signaling complexes are assembled at the aNKIS, but are not present at the iNKIS. While formation of the aNKIS requires excessive remodeling of cortical and cytoplasmic cytoskeleton, the iNKIS does not require rearrangements of cytoskeleton or cytoplasmic structures on a large scale. Interestingly, Lck, Itk, PKCθ and ZAP70 are found to partially co-localize with MTOC, indicating that a subset of these proteins interacts with MTOC and may be transported with MTOC to the IS.
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Riteau B., Barber D.F., and Long E.O. Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. J Exp Med 198 (2003) 469-474
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Perez O.D., Mitchell D., Jager G.C., and Nolan G.P. LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. Blood 104 (2004) 1083-1093
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Chen X., Allan D.S.J., Krzewski K., Ge B., Kopcow H., and Strominger J.L. CD28-stimulated ERK2 phosphorylation is required for polarization of the microtubule organizing center and granules in YTS NK cells. Proc Natl Acad Sci U S A 103 (2006) 10346-10351
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Resting NK cells can be induced to cytotoxicity and production cytokines by ligation of specific and synergistic receptor combinations. In resting cells, cytotoxicity can be only induced by cross-linking of CD16. NKp46 alone is not sufficient to induce NK response, but it can synergize with other receptors (2B4, NKG2D, CD2, and DNAM1) to provide full activation of NK cells. 2B4 synergizes with NKp46, NKG2D and DNAM1; NKG2D synergizes only with NKp46 and 2B4, while DNAM1 synergizes with NKp46 and 2B4. CD2 synergizes only with NKp46 to induce NK cell activation. Thus, NK cells use combination of synergistic activating receptors to facilitate cytotoxic responses.
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Exocytosis of secretory lysosomes depends on calcium release and is enhanced by the contact with target cells. NK cells contain a pool of lysosomes that are ready for secretion, but contact and recognition of a target cell results in quick de novo synthesis of secretory lysosomes. The biogenesis of lysosomes is dependent on PCK activity, but not on TGN network. Authors propose that secretory lysosomes are derived from late endosomal or still unknown pathway.
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Liu D., Xu L., Yang F., Li D., Gong F., and Xu T. Rapid biogenesis and sensitization of secretory lysosomes in NK cells mediated by target-cell recognition. Proc Natl Acad Sci U S A 102 (2005) 123-127. Exocytosis of secretory lysosomes depends on calcium release and is enhanced by the contact with target cells. NK cells contain a pool of lysosomes that are ready for secretion, but contact and recognition of a target cell results in quick de novo synthesis of secretory lysosomes. The biogenesis of lysosomes is dependent on PCK activity, but not on TGN network. Authors propose that secretory lysosomes are derived from late endosomal or still unknown pathway.
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Cdc42-interacting protein-4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse
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Following NK cell activation, CIP4 translocates to MTOC and is able to interact with WASp and the cortical actin meshwork. Thus, following NK cell activation CIP4 can facilitate MTOC localization and/or MTOC anchoring at the IS, and can provide a link between MT and F-actin network, through its ability to interact with WASp and Cdc42. CIP4 knockdown inhibits MTOC polarization, but does not affect actin accumulation at the NKIS or Cdc42 activation, indicating that CIP4 lies downstream of Cdc42 activation, actin accumulation/polarization, and synapse formation but is crucial, at later stages of cytotoxicity, for MTOC and granule polarization to the IS.
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Banerjee P.P., Pandey R., Zheng R., Suhoski M.M., Monaco-Shawver L., and Orange J.S. Cdc42-interacting protein-4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse. J Exp Med 204 (2007) 2305-2320. Following NK cell activation, CIP4 translocates to MTOC and is able to interact with WASp and the cortical actin meshwork. Thus, following NK cell activation CIP4 can facilitate MTOC localization and/or MTOC anchoring at the IS, and can provide a link between MT and F-actin network, through its ability to interact with WASp and Cdc42. CIP4 knockdown inhibits MTOC polarization, but does not affect actin accumulation at the NKIS or Cdc42 activation, indicating that CIP4 lies downstream of Cdc42 activation, actin accumulation/polarization, and synapse formation but is crucial, at later stages of cytotoxicity, for MTOC and granule polarization to the IS.
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