Spatially resolved in silico modeling of NKG2D signaling kinetics suggests a key role of NKG2D and Vav1 Co-clustering in generating natural killer cell activation

by Rajdeep Kaur Grewal, Jayajit Das

Natural Killer (NK) cells provide key resistance against viral infections and tumors. A diverse set of activating and inhibitory NK cell receptors (NKRs) interact with cognate ligands presented by target host cells, where integration of dueling signals initiated by the ligand-NKR interactions dete rmines NK cell activation or tolerance. Imaging experiments over decades have shown micron and sub-micron scale spatial clustering of activating and inhibitory NKRs. The mechanistic roles of these clusters in affecting downstream signaling and activation are often unclear. To this end, we developed a preDISCLOSUREdictive in silico framework by combining spatially resolved mechanistic agent based modeling, published TIRF imaging data, and parameter estimation to determine mechanisms by which formation and spatial movements of activating NKG2D microclusters affect early time NKG2D signaling kine tics in a human cell line NKL. We show co-clustering of NKG2D and the guanosine nucleotide exchange factor Vav1 in NKG2D microclusters plays a dominant role over ligand (ULBP3) rebinding in increasing production of phospho-Vav1(pVav1), an activation marker of early NKG2D signaling. The in silico mod el successfully predicts several scenarios of inhibition of NKG2D signaling and time course of NKG2D spatial clustering over a short (~3 min) interval. Modeling shows the presence of a spatial positive feedback relating formation and centripetal movements of NKG...

Source: PLoS Computational Biology - May 18, 2022 Category: Biology Authors: Rajdeep Kaur Grewal Source Type: research