Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection

Jiang, Hongsi; Fan, Ping; Erickson, Laurie; Jang, Mei Shiang; Sanui, Terukazu; Kunisaki, Yuya; Sasazuki, Takehiko; Kobayashi, Masakazu; Fukui, Yoshihiro

doi:10.1084/jem.20050911

Cited by 43 publications

(40 citation statements)

References 51 publications

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“…3B). These results suggest that DOCK2 deficiency suppresses Con A-induced hepatitis not only by reducing V␣14 NKT cells in the liver, but also by attenuating activation of conventional T cells (31,38).…”

Section: Dock2 ϫ/ϫ Mice Are Resistant To Con A-induced Hepatitismentioning

confidence: 79%

DOCK2 Is Required in T Cell Precursors for Development of Vα14 NK T Cells

Kunisaki

Tanaka

Sanui

et al. 2006

The Journal of Immunology

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Mouse CD1d-restricted Vα14 NKT cells are a unique subset of lymphocytes, which play important roles in immune regulation, tumor surveillance and host defense against pathogens. DOCK2, a mammalian homolog of Caenorhabditis elegans CED-5 and Drosophila melanogaster myoblast city, is critical for lymphocyte migration and regulates T cell responsiveness through immunological synapse formation, yet its role in Vα14 NKT cells remains unknown. We found that DOCK2 deficiency causes marked reduction of Vα14 NKT cells in the thymus, liver, and spleen. When α-galactosylceramide (α-GalCer), a ligand for Vα14 NKT cells, was administrated, cytokine production was scarcely detected in DOCK2-deficient mice, suggesting that DOCK2 deficiency primarily affects generation of Vα14 NKT cells. Supporting this idea, staining with CD1d/α-GalCer tetramers revealed that CD44−NK1.1− Vα14 NKT cell precursors are severely reduced in the thymuses of DOCK2-deficient mice. In addition, studies using bone marrow chimeras indicated that development of Vα14 NKT cells requires DOCK2 expression in T cell precursors, but not in APCs. These results indicate that DOCK2 is required for positive selection of Vα14 NKT cells in a cell-autonomous manner, thereby suggesting that avidity-based selection also governs development of this unique subset of lymphocytes in the thymus.

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Section: Dock2 ϫ/ϫ Mice Are Resistant To Con A-induced Hepatitismentioning

confidence: 79%

DOCK2 Is Required in T Cell Precursors for Development of Vα14 NK T Cells

Kunisaki

Tanaka

Sanui

et al. 2006

The Journal of Immunology

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“…Dock2-deficient lymphocytes show greatly reduced entry, egress and interstitial motility in lymphoid and non-lymphoid tissues. In murine models of cardiac allograft rejection and diabetes, deletion of Dock2 in lymphocytes was found to be protective, pointing to a role for Dock2 in migration of pathogenic T cells (7, 8). Over the past decade, Dock2 has also been found to regulate a range of Rac-dependent functions in neutrophils, dendritic cells and NKT cells (9-12).…”

Section: Introductionmentioning

confidence: 99%

Essential Role of Elmo1 in Dock2-Dependent Lymphocyte Migration

Stevenson

Rosa

Anderson

et al. 2014

The Journal of Immunology

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Elmo1 and Elmo2 are highly homologous cytoplasmic adapter proteins that interact with Dock family guanine nucleotide exchange factors to promote activation of the small GTPase Rac. In T lymphocytes, Dock2 is essential for CCR7- and CXCR4-dependent Rac activation and chemotaxis, but the role of Elmo proteins in regulating Dock2 function in primary T cells is not known. Here we show that endogenous Elmo1 but not Elmo2 interacts constitutively with Dock2 in mouse and human primary T cells. CD4+ T cells from Elmo1−/− mice were profoundly impaired in polarization, Rac activation and chemotaxis in response to CCR7 and CXCR4 stimulation. Transfection of full-length Elmo1, but not Elmo2 or a Dock2-binding mutant of Elmo1, rescued defective migration of Elmo1−/− T cells. Interestingly, Dock2 protein levels were reduced by four-fold in Elmo1−/− lymphocytes despite normal levels of Dock2 mRNA. Dock2 polyubiquitination was increased in Elmo1−/− T cells, and treatment with proteasome inhibitors partially restored Dock2 levels in Elmo1−/− T cells. Finally, we show that Dock2 is directly ubiquitinated in CD4+ T cells and that Elmo1 expression in heterologous cells inhibits ubiquitination of Dock2. Taken together, these findings reveal a previously unknown, non-redundant role for Elmo1 in controlling Dock2 levels and Dock2-dependent T cell migration in primary lymphocytes. Inhibition of Dock2 has therapeutic potential as a means to control recruitment of pathogenic lymphocytes in diseased tissues. This work provides valuable insights into the molecular regulation of Dock2 by Elmo1 that can be used to design improved inhibitors that target the Elmo-Dock-Rac signaling complex.

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“…A knockout study against DOCK2 demonstrated the alternative role of DOCK2, regarding murine T-and B-cell motility [5] and control of the cardiac transplant rejection in mice [6]. The prominent roles of DOCK2, such as immune modulation associated with T cell differentiation [7; 8] and neutrophil chemotaxis [9; 10] were also disclosed.…”

Section: Introductionmentioning

confidence: 99%