Natural Killer Cells
Chris Nevares & Michael Murphy
http://www.nida.nih.gov/NIDA_notes/NNvol21N6/killercell.jpg
NK cells have a common precursor to other lymphocytes, but it is not known what causes differentiation of NK cells as opposed to T or B cells.
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
Activating receptor stimulated
Inhibition receptor stimulated
Result
Yes No Kills cell
No No does not kill cell
Yes Yes Does not kill cell
No Yes Does not kill cell
NK cell receptor stimulations and resulting responses
Dynamin 2 Regulates Granule Exocytosis during NK
Cell-Mediated Cytotoxicity1
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 machineryo 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 cytotoxicityo 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
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