Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration.
Proc Natl Acad Sci U S A 2015 Mar 10; 112(10):3056-61.
Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function. Proc Natl Acad Sci U S A 2015 Mar 10; 112(10):3056-61.
Krishnaswamy, Jayendra Kumar; Singh, Arpita; Gowthaman, Uthaman; Wu, Renee; Gorrepati, Pavane; Sales Nascimento, Manuela; Gallman, Antonia; Liu, Dong; Rhebergen, Anne Marie; Calabro, Samuele; Xu, Lan; Ranney, Patricia; Srivastava, Anuj; Ranson, Matthew; Gorham, James D; McCaw, Zachary; Kleeberger, Steven R; Heinz, Leonhard X; Müller, André C; Bennett, Keiryn L; Superti-Furga, Giulio; Henao-Mejia, Jorge; Sutterwala, Fayyaz S; Williams, Adam; Flavell, Richard A; and Eisenbarth, Stephanie C, "Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration." (2015). Faculty Research 2015. 47.