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Coincidental Loss of DOCK8 Function in NLRP10-Deficient and C3H/Hej Mice Results in Defective Dendritic Cell Migration

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Coincidental Loss of DOCK8 Function in NLRP10-Deficient and C3H/Hej Mice Results in Defective Dendritic Cell Migration Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration Jayendra Kumar Krishnaswamya,b,1, Arpita Singha,b,1, Uthaman Gowthamana,b, Renee Wua,b, Pavane Gorrepatia,b, Manuela Sales Nascimentoa,b, Antonia Gallmana,b, Dong Liua,b, Anne Marie Rhebergenb, Samuele Calabroa,b, Lan Xua,b, Patricia Ranneya,b, Anuj Srivastavac, Matthew Ransond, James D. Gorhamd, Zachary McCawe, Steven R. Kleebergere, Leonhard X. Heinzf, André C. Müllerf, Keiryn L. Bennettf, Giulio Superti-Furgaf, Jorge Henao-Mejiag, Fayyaz S. Sutterwalah, Adam Williamsi, Richard A. Flavellb,j,2, and Stephanie C. Eisenbartha,b,2 Departments of aLaboratory Medicine and bImmunobiology and jHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520; cComputational Sciences, The Jackson Laboratory, Bar Harbor, ME 04609; dDepartment of Pathology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755; eNational Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; fCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; gInstitute for Immunology, Departments of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; hInflammation Program, Department of Internal Medicine, University of Iowa, Iowa City, IA 52241; and iThe Jackson Laboratory for Genomic Medicine, Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06032 Contributed by Richard A. Flavell, January 28, 2015 (sent for review December 23, 2014; reviewed by Matthew L. Albert and Thirumala-Devi Kanneganti) Dendritic cells (DCs) are the primary leukocytes responsible for NLRP10 is the only NOD-like receptor (NLR) without a leu- priming T cells. To find and activate naïve T cells, DCs must migrate cine-rich repeat domain, the putative pathogen-associated molecu- to lymph nodes, yet the cellular programs responsible for this key lar pattern (PAMP)–binding domain. It has been proposed to both step remain unclear. DC migration to lymph nodes and the subse- positively and negatively regulate other NLRs, such as NOD1 and quent T-cell response are disrupted in a mouse we recently described NLRP3, respectively (5, 6). Although we found that NLRP3 lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain con- inflammasome activation was unaltered in the absence of NLRP10, INFLAMMATION − − IMMUNOLOGY AND taining 10); however, the mechanism by which this pattern recogni- we discovered that Nlrp10 / mice could not mount a productive tion receptor governs DC migration remained unknown. Using T- or B-cell immune response due to a DC-intrinsic failure to a proteomic approach, we discovered that DCs from Nlrp10 knock- emigrate out of inflamed tissues (4, 7). out mice lack the guanine nucleotide exchange factor DOCK8 (dedi- To understand the mechanism by which NLRP10 governs DC cator of cytokinesis 8), which regulates cytoskeleton dynamics in migration, we used an expression proteomic approach to identify multiple leukocyte populations; in humans, loss-of-function mutations Dock8 Nlrp10 in result in severe immunodeficiency. Surprisingly, Significance knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout Understanding dendritic cell (DC) migration during an immune strain harbored an unexpected mutation in Dock8, which was con- response is fundamental to defining the rules that govern T cell- firmed using whole-exome sequencing. Consistent with our orig- mediated immunity. We recently described mice deficient in the inal report, NLRP3 inflammasome activation remained unaltered in pattern recognition receptor NLRP10 (NLR family, pyrin domain NLRP10-deficient DCs even after restoring DOCK8 function; how- containing 10) with a severe DC migration defect. Using whole- ever, these DCs recovered the ability to migrate. Isolated loss of exome sequencing, we discovered that this defect was due to DOCK8 via targeted deletion confirmed its absolute requirement for mutation of the guanine nucleotide exchange factor Dock8 DC migration. Because mutations in Dock genes have been discov- (dedicator of cytokinesis 8). DOCK8 regulates cytoskeleton dy- ered in other mouse lines, we analyzed the diversity of Dock8 across namics in leukocytes, and loss-of-function mutations cause an different murine strains and found that C3H/HeJ mice also harbor immunodeficiency syndrome. Mutations in other Dock genes have a Dock8 mutation that partially impairs DC migration. We con- been reported in mice lacking innate immune pathways, and we clude that DOCK8 is an important regulator of DC migration during now report two more lines with Dock8 mutations resulting in an immune response and is prone to mutations that disrupt its impaired DC migration. These results clarify the role of NLRP10 crucial function. in DCs and confirm the essential function of DOCK8 in the immune system. dendritic cell | NLRP10 | DOCK8 | C3H/HeJ | CDC42 Author contributions: J.K.K., A. Singh, U.G., R.W., P.G., M.S.N., A.G., D.L., A.M.R., S.C., endritic cells (DCs) are crucial for the initiation of an adaptive L.X.H., J.H.-M., F.S.S., A.W., and S.C.E. designed research; J.K.K., A. Singh, U.G., R.W., P.G., Dimmune response. Upon acquiring antigens in the periphery, M.S.N., A.G., D.L., A.M.R., S.C., L.X., P.R., M.R., L.X.H., A.C.M., K.L.B., A.W., and S.C.E. per- formed research; G.S.-F., J.H.-M., A.W., R.A.F., and S.C.E. contributed new reagents/analytic DCs undergo a maturation process that includes antigen processing, tools; J.K.K., A. Singh, U.G., R.W., M.S.N., A.G., D.L., A.M.R., S.C., L.X., P.R., A. Srivastava, M.R., cytokine production, and up-regulation of costimulatory molecules. J.D.G., Z.M., S.R.K., L.X.H., A.C.M., K.L.B., G.S.-F., F.S.S., A.W., R.A.F., and S.C.E. analyzed data; A mature DC must then migrate from peripheral tissues to draining and J.K.K., A. Singh, U.G., R.W., and S.C.E. wrote the paper. lymph nodes (LNs) to fulfill its role as an antigen-presenting cell Reviewers: M.L.A., Institut Pasteur; and T.-D.K., St. Jude Children’s Research Hospital. that primes naïve T cells (1). Although the signals that induce this The authors declare no conflict of interest. maturation process are now well-established (1), relatively little is Data deposition: The sequence reported in this paper has been deposited in the National Center for Biotechnology Information Sequence Read Archive, www.ncbi.nlm.nih.gov/sra understood about DC migration aside from the primary chemo- (accession no. SRR1792904). tactic cue provided by CCR7 that guides DCs to the LN (2, 3). 1J.K.K. and A. Singh contributed equally to this work. We recently described a genetically modified NLRP10 (NLR 2To whom correspondence may be addressed. Email: [email protected] or family, pyrin domain containing 10) knockout strain in which this [email protected]. migration step was disrupted while leaving the remainder of the This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. DC maturation program, including CCR7 expression, intact (4). 1073/pnas.1501554112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1501554112 PNAS Early Edition | 1of6 Downloaded by guest on September 27, 2021 molecules with altered expression in DCs generated from the WT Nlrp10-/- −/− A Nlrp10 strain and discovered a profound reduction in DOCK8 400 400 (dedicator of cytokinesis 8). DOCK8 is a guanine nucleotide m) 300 300 μ m/sec) exchange factor (GEF) that has two functional domains, DOCK μ 200 200 homology region (DHR) 1 and DHR2 (8). In murine DCs, the 100 100 DHR2 domain has been implicated in regulating the Rho GTPase y-axis ( CDC42 (cell division control protein 42 homolog), which in turn 0 0 Speed ( -100 0 100 -100 0 100 WT Nlrp10-/- maintains cell polarity of mature DCs during migration (9, 10). x-axis (μm) Furthermore, mice harboring inactivating mutations in Dock8 lack marginal zone B-cell development, long-term antibody production B Unstimulated LPS stimulated + following immunization, and memory CD8 T-cell responses to viral infections (11, 12). In humans, inactivating mutations in Dock8 were recently identified as the primary genetic cause underlying autosomal recessive hyper-IgE syndrome (13). This syndrome presents with eczema, recurrent infections of the skin and re- (mean ratio ko/wt) spiratory tract, increased serum IgE, eosinophilia, recurrent fungal 2 and viral infections, extensive food and environmental allergies, log and, in certain patients, squamous cell dysplasia and carcinomas (14). C D WT Nlrp10-/- Given that DOCK8 regulates a wide array of immunologic kDa 250 processes in mouse and human, we sought to understand how Dock8 150 DOCK8 NLRP10 regulates DOCK8. To our surprise, we discovered that − − 100 loss of DOCK8 in the Nlrp10 / strain was secondary to a point 50 mutation within the Dock8 gene itself. In this study, we dem- β −/− 37 -Actin onstrate that restoring DOCK8 function in the Nlrp10 strain Fold induction 25 leads to normal DC migration in vivo. We further show that LPS - + - + LPS - ++- ++ deletion of Dock8, as well as spontaneous mutation of Dock8 in -/- WT Nlrp10 CCL19 --++ - - another inbred strain of mice, results in defective DC migration and, depending on the degree of impaired migration, also abro- + E Gated on splenic B cells gates CD4 T-cell activation. 10.7 0.7 Results Reduced Expression of the GEF DOCK8 in NLRP10-Deficient Mice. De- spite clear evidence demonstrating failed movement of adoptively −/− transferred Nlrp10 bone marrow-derived dendritic cells (BMDCs) CD21 WT Nlrp10-/- in vivo, classical assays to measure their migration in vitro, such as CD23 Transwell chambers, found no defect (4).
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