DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

Zhang, Qian; Dove, Christopher G.; Hor, Jyh Liang; Murdock, H. Moses; Strauss‐Albee, Dara M.; García, Juan Ruiz; Mandl, Judith N.; Grodick, Rachael A.; Jing, Huie; Chandler-Brown, Devon; Lenardo, Timothy E.; Crawford, Greg; Matthews, Helen; Freeman, Alexandra F.; Cornall, Richard J.; Germain, Ronald N.; Mueller, Scott N.; Su, Helen C.

doi:10.1083/jcb.2075oia223

Cited by 39 publications

(74 citation statements)

References 44 publications

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“…3E) (4, 9). Dock8 mutations in humans are responsible for a rare form of immunodeficiency, autosomal recessive hyper-IgE syndrome, which affects both T-cell and B-cell function (13,28,29). The effect of Dock8 mutation on human DC migration and the subsequent impact on adaptive immune responses, however, remain unanswered questions.…”

Section: C3h/hejmentioning

confidence: 99%

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

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.D endritic cells (DCs) are crucial for the initiation of an adaptive immune response. Upon acquiring antigens in the periphery, DCs undergo a maturation process that includes antigen processing, cytokine production, and up-regulation of costimulatory molecules. A mature DC must then migrate from peripheral tissues to draining lymph nodes (LNs) to fulfill its role as an antigen-presenting cell that primes naïve T cells (1). Although the signals that induce this maturation process are now well-established (1), relatively little is understood about DC migration aside from the primary chemotactic cue provided by CCR7 that guides DCs to the LN (2, 3).We recently described a genetically modified NLRP10 (NLR family, pyrin domain containing 10) knockout strain in which this migration step was disrupted while leaving the remainder of the DC maturation program, including CCR7 expression, intact (4).NLRP10 is the only NOD-like receptor (NLR) without a leucine-rich repeat domain, the putative pathogen-associated molecular pattern (PAMP)-binding domain. It has been proposed to both positively and negatively regulate other NLRs, such as NOD1 and NLRP3, respectively (5, 6). Although we found that NLRP3 inflammasome activation was unaltered in the absence of NLRP10, we discovered that Nlrp10 −/− mice could ...

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Section: C3h/hejmentioning

confidence: 99%

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

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…The majority of these patients have low numbers of CD4 + and CD8 + T cells in the blood. DOCK8 has been shown to regulate B, T, NKT, and NK cells and DCs functions in mice (17,(20)(21)(22)(23)(24)(25)(26). We have recently uncovered a poten-…”

Section: Introductionmentioning

confidence: 99%

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

Singh¹,

Eken²,

Hagin³

et al. 2017

JCI Insight

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“…+ T cells and DCs show impaired migration through tissues (14,16,46). Localization of Tregs in T cell-rich areas of LNs is important for controlling autoreactive Teff clones (45).…”

Section: Dock8-deficient Tregs Form An Unstable Is and Have Decreasedmentioning

confidence: 99%

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

et al. 2017

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DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

Cited by 39 publications

References 44 publications

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

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

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