Cutting Edge: NK Cell Licensing Modulates Adhesion to Target Cells

Abstract

Binding of natural killer (NK) cell inhibitory receptors to MHC-I confers increased responsiveness to NK cells by a process known as NK cell licensing/education. Reduced MHC-I expression or a lack of inhibitory receptors for MHC-I results in diminished NK cell responsiveness. In this study, we evaluated the effect of human and mouse NK cell licensing on early stages of natural cytotoxicity. Unlicensed NK cells did not form as many stable conjugates with target cells. The reduction of NK cell conjugation to target cells was not attributed to altered β2 integrin LFA-1 properties but was instead due to reduced inside-out signaling to LFA-1 by activating receptors. For those unlicensed NK cells that did form conjugates, LFA-1-dependent granule polarization was similar to that in licensed NK cells. Thus, licensing controls signals as proximal as inside-out signaling by activating receptors but not integrin outside-in signaling for granule polarization.

Microchip-Based Single-Cell Imaging Reveals That CD56dimCD57−KIR−NKG2A+ NK Cells Have More Dynamic Migration Associated with Increased Target Cell Conjugation and Probability of Killing Compared to CD56dimCD57−KIR−NKG2A− NK Cells

“…The observed difference in migration behavior between the subsets could partly explain our observation that NKG2A + NK cells form more conjugates because increased motility is likely to lead to more frequent encounters with target cells. An additional contribution to the increased conjugation for the NKG2A + subset could come from elevated expression of the open, active form of LFA-1, which has been associated with NK cell education through increased insideout signaling by activating receptors to LFA-1 (15) and coordinated expression with DNAM-1 in the immune synapse (20). This is supported by our observation that nonlytic conjugates formed by IR 2 NK cells were shorter than those formed by NKG2A + NK cells.…”

“…In addition, uneducated NK cells have been found to be equally functional as educated NK cells in secretion of IFN-g during Listeria monocytogenes infection and are the primary mediators in suppression of mouse CMV infection (13,14). A recent study revealed that the diminished cytotoxicity of uneducated NK cells is not due to compromised granule polarization but can be partially explained by reduced inside-out signaling leading to weaker LFA-1-dependent adhesion and failure to form stable conjugates with target cells (15). Still, little is known about how education of NK cells influences different aspects of NK cell cytotoxicity such as migration and efficacy of activation and killing when encountering target cells.…”

Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing

“…Significant difference between MGUS and MM (Pearson's x2, Fisher's exact or Mann-Whitney tests). 4 Risk factors (0/1/2 score) in MGUS and SMM, and international scoring system (ISS, I/II/III score) in MM.…”

“…3,4 KIR receptors may transmit inhibitory (iKIRs) or activating (aKIRs) signals. 5 Within the iKIRs, KIR2DL1 recognizes the HLA-C2 allotype (Lys80), and KIR2DL2/3 the HLA-C1 allotype (Asn80), 6 although KIR2DL2 may also interact with the HLA-C2 allotype.…”

Coordinated Expression of DNAM-1 and LFA-1 in Educated NK Cells

“…Thus, a unique feature of educated NK cells may be their confinement of activating receptors, including the natural cytotoxicity receptor NKp46, in nanodomain-like structures (9). Such membrane organization of activating receptors may influence signaling and, as a consequence, the ability of educated cells to form conjugates and engage in downstream functional responses (11).…”