Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Moretti, Federico A.; Moser, Markus; Lyck, Ruth; Abadier, Michael; Ruppert, Raphael; Engelhardt, Britta; Fässler, Reinhard

doi:10.1073/pnas.1316032110

Cited by 48 publications

(55 citation statements)

References 34 publications

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“…The role of kindlin-3 in the activation and functions of leukocyte integrins was corroborated with intravital imaging of TNF-α-stimulated cremaster-muscle venules, which revealed that adhesion of leukocytes to inflamed endothelial cells was dramatically impaired (Moser et al, 2009a). In effector T cells, the kindlin-3-mediated integrin activation step appears to be particularly important when the expression levels of integrin ligands on endothelial cells are low (Moretti et al, 2013;Morrison et al, 2013). Hence, in experimental autoimmune encephalitis (EAE), a model for multiple sclerosis with a high expression of integrin ligand in the inflamed tissue, inhibition of kindlin-3 is probably not sufficient to block extravasation of autoreactive T cells and disease progression (Moretti et al, 2013).…”

Section: Kindlin-3 In Hematopoietic Dysfunctions and Lad IIImentioning

confidence: 81%

“…In effector T cells, the kindlin-3-mediated integrin activation step appears to be particularly important when the expression levels of integrin ligands on endothelial cells are low (Moretti et al, 2013;Morrison et al, 2013). Hence, in experimental autoimmune encephalitis (EAE), a model for multiple sclerosis with a high expression of integrin ligand in the inflamed tissue, inhibition of kindlin-3 is probably not sufficient to block extravasation of autoreactive T cells and disease progression (Moretti et al, 2013). Kindlin-3 is also required for B-cell adhesion under flow (Willenbrock et al, 2013), trafficking into lymph nodes and immunoglobulin expression (Morrison et al, 2015).…”

Section: Kindlin-3 In Hematopoietic Dysfunctions and Lad IIImentioning

confidence: 99%

See 1 more Smart Citation

The kindlin family: functions, signaling properties and implications for human disease

Rognoni

Ruppert

Fässler

2016

Journal of Cell Science

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192

186

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The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation.

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Section: Kindlin-3 In Hematopoietic Dysfunctions and Lad IIImentioning

confidence: 81%

Section: Kindlin-3 In Hematopoietic Dysfunctions and Lad IIImentioning

confidence: 99%

The kindlin family: functions, signaling properties and implications for human disease

Rognoni

Ruppert

Fässler

2016

Journal of Cell Science

Self Cite

192

186

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“…Similarly, deletion of the cytoskeletal regulators Rap1, RIAM, talin, or RAPL impair chemokine-stimulated ICAM-1 adhesion and naïve T-cell trafficking (52)(53)(54), whereas CRK proteins regulate T-cell adhesion, chemotaxis, and diapedesis, leading to reduced T-cell trafficking selectively to inflamed tissues (55). In contrast, recent reports show that Kindlin-3 is not required for diapedesis, although it has been shown to play an important role in adhesion and CNS trafficking more generally (56,57).…”

Section: Discussionmentioning

confidence: 99%

Ena/VASP proteins regulate activated T-cell trafficking by promoting diapedesis during transendothelial migration

Estin

Thompson

Traxinger

et al. 2017

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

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Vasodilator-stimulated phosphoprotein (VASP) and Ena-VASP-like (EVL) are cytoskeletal effector proteins implicated in regulating cell morphology, adhesion, and migration in various cell types. However, the role of these proteins in T-cell motility, adhesion, and in vivo trafficking remains poorly understood. This study identifies a specific role for EVL and VASP in T-cell diapedesis and trafficking. We demonstrate that EVL and VASP are selectively required for activated T-cell trafficking but are not required for normal T-cell development or for naïve T-cell trafficking to lymph nodes and spleen. Using a model of multiple sclerosis, we show an impairment in trafficking of EVL/VASP-deficient activated T cells to the inflamed central nervous system of mice with experimental autoimmune encephalomyelitis. Additionally, we found a defect in trafficking of EVL/VASP double-knockout (dKO) T cells to the inflamed skin and secondary lymphoid organs. Deletion of EVL and VASP resulted in the impairment in α4 integrin (CD49d) expression and function. Unexpectedly, EVL/VASP dKO T cells did not exhibit alterations in shear-resistant adhesion to, or in crawling on, primary endothelial cells under physiologic shear forces. Instead, deletion of EVL and VASP impaired T-cell diapedesis. Furthermore, T-cell diapedesis became equivalent between control and EVL/VASP dKO T cells upon α4 integrin blockade. Overall, EVL and VASP selectively mediate activated T-cell trafficking by promoting the diapedesis step of transendothelial migration in a α4 integrin-dependent manner.A ctivated T-cell trafficking across the vascular endothelium is essential for ongoing immune surveillance of tissues and for effective immune responses to conditions such as infection and cancer. Conversely, in situations of immune dysregulation, inhibition of self-reactive T-cell trafficking represents a promising target for therapeutic immunomodulation. Disruption of these pathways, such as by antibody blockade of α4 integrins, is a highly effective approach to immunomodulation (1, 2). However, the molecular mechanisms by which chemokine receptor and adhesion molecule signaling induce the T-cell cytoskeletal machinery to promote extravasation are not yet fully elucidated.Transendothelial migration (TEM), the process by which T cells extravasate from the blood into tissues, is characterized by four distinct steps: rolling along the vascular wall, arrest or adhesion, intravascular crawling, and diapedesis across the endothelial barrier (3). Surface adhesion molecules play well-characterized roles in each step of the process. For example, the initial rolling step of TEM is facilitated by interactions between T-cell and endothelial selectins, whereas the adhesion, intravascular crawling, and diapedesis steps of TEM are mainly regulated by chemokineand shear force-stimulated modulation of lymphocyte functionassociated antigen 1 (LFA-1, αLβ2 integrin, CD11a/CD18) and very late antigen 4 (VLA-4, α4β1 integrin, CD49d/CD29) interactions with intracellular adhesion molecule 1 ...

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“…Kindlins provide a physical link between the integrin and the cortical actin cytoskeleton and are thought to be involved in integrin conformational change to the active, fully open state, as well as contributing to downstream integrin signaling (17). In lymphocytes, kindlin-3 binds LFA-1 and is essential for firm adhesion of both T and B cells (18)(19)(20), and it stabilizes integrin/ligand interactions in T cells following TCR engagement in vitro (21). Meanwhile, 14-3-3 proteins bind to the TTT site when one or more of the T residues are phosphorylated (e.g., after T cell activation by phorbol esters) and initiate downstream integrin signaling (22).…”

Section: Discussionmentioning

confidence: 99%

Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function–Associated Antigen-1 and Kindlin-3

Morrison

Uotila

Asens

et al. 2015

The Journal of Immunology

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Kindlin-3 is an important integrin regulator that is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, a disorder characterized by defective neutrophil trafficking and platelet function, leading to recurrent bacterial infections and bleeding. Kindlin-3 is also known to regulate T cell adhesion in vitro and trafficking in vivo, but whether the integrin/kindlin interaction regulates T or B cell activation in vivo is unclear. In this study, we used TTT/AAA β2-integrin knock-in (KI) mice and TCR-transgenic (OT-II) KI mice, in which the integrin/kindlin connection is disrupted, to investigate the role of the integrin/kindlin interaction in T cell activation. We show that basal T cell activation status in these animals in vivo is normal, but they display reduced T cell activation by wild-type Ag-loaded dendritic cells in vitro. In addition, T cell activation in vivo is reduced. We also show that basal Ab levels are normal in TTT/AAA β2-integrin KI mice, but B cell numbers in lymph nodes and IgG and IgM production after immunization are reduced. In conclusion, we show that the integrin/kindlin interaction is required for trafficking of immune cells, as well as for T cell activation and B cell Ab responses in vivo. These results imply that the immunodeficiency found in leukocyte adhesion deficiency type III patients, in addition to being caused by defects in neutrophil function, may be due, in part, to defects in lymphocyte trafficking and activation.

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Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Cited by 48 publications

References 34 publications

The kindlin family: functions, signaling properties and implications for human disease

The kindlin family: functions, signaling properties and implications for human disease

Ena/VASP proteins regulate activated T-cell trafficking by promoting diapedesis during transendothelial migration

Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function–Associated Antigen-1 and Kindlin-3

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