Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Abstract Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naive 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 domaincontaining 10); however, the mechanism by which this pattern recognition receptorgoverns DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10knockout 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 Dock8result in severe immunodeficiency. Surprisingly, Nlrp10knockout mice crossed to other backgrounds had normal DOCK8expression. This suggested that the original Nlrp10knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole- exome sequencing. Consistent with our original report, NLRP3 inflammasomeactivation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8via 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 Dock8across different murine strains and found that C3H/HeJ mice also harbor a Dock8mutation that partially impairs DC migration. We conclude that DOCK8is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.