Receptors of NK Cells NK cells do not possess antigen specific receptors. They have two different categories of receptors: – Lectin-like – killer-cell immunoglobulin-like receptors (KIR) Though the structure does not define function.
Receptors on NK cells exhibit activation and inhibition functions – Rather than binding to antigen, NK cells have different types of receptors that activate or inhibit their function. Current theory states there are multiple activating and inhibiting receptors on each NK cell Activating receptors exhibit immunoreceptor tyrosine activating motifs (ITAM) while inhibition receptors exhibit immunoreceptor tyrosine inhibition motifs (ITIM) – Basically ITAMs help deliver activation signals, and ITIMs repress them
NK cells tend to target cells missing Class I MHC
Activating receptor stimulated Inhibition receptor stimulated Result YesNoKills cell No does not kill cell Yes Does not kill cell NoYesDoes not kill cell NK cell receptor stimulations and resulting responses
Granules are composed of perforin and granzymes
Dynamin 2 Regulates Granule Exocytosis during NK Cell-Mediated Cytotoxicity 1 Laura N. Arneson,* Colin M. Segovis,* Timothy S. Gomez,*† Renee A. Schoon,* Christopher J. Dick,* Zhenkun Lou,† Daniel D. Billadeau,2*† and Paul J. Leibson*
What is Dynamin 2? Dyn2 has five functional domains: 1.GTPase domain 2.Oligomerization domain 3.Pleckstrin homology domain 4.GTPase effector domain 5.Proline-rich domain implicated in in interacting with Src homology 3 (SH3) domains
What does Dyn2 do? Regulates: Endo/exocytosis Actin assembly Interacts with: Actin remodeling machinery o Cortactin, Grb2, and Nck Vav1 o T-cell activation & actin polymerization t-SNARE and Vam3p [Vps1p (yeast homologue)] o Vacuole fusion
Summary of paper findings 1.Dyn2 regulates NK cell-mediated cytotoxicity o Controls exocytosis of lytic granules 2.Suppression of Dyn2 impairs cell-mediated cytotoxicity 3.Dyn2 effects independent of proximal signaling 4.Dyn2 regulates terminal phase of granule release 5.Novel function of protein in exocytosis o Endocytosis well characterized 6.May participate in broader cell regulation
Dyn2 localizes with lytic granules at the NK cytolytic synapse
Discussion Surprising role in exocytosis Coordination of fission with fusion Dyn2 involved in insulin secretion CTL homologue Muc 13-4 required for vesicle fusion Dyn2 in NK cells not required for secretion In absence of Dyn2: Initial burst occurs, but subsequent bursts limited Finite number of granule fission sites at synapse Ineffective removal of empty lytic vesicles Kiss-and-run model or cavicapture may explain this phenomena
Kiss and Run Model http://www.neuroworld.it/aBC/kis_run.htm
Dyn2 in medicine Charcot-Marie-Tooth disease One of the most common inherited neurodegenerative diseases Centronuclear myopathy Improper localization of the nucleus X-linked
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