The Kindlin 3 Pleckstrin Homology Domain Has an Essential Role in Lymphocyte Function-associated Antigen 1 (LFA-1) Integrin-mediated B Cell Adhesion and Migration

Hart, Rosie; Stanley, Paula; Chakravarty, Probir; Hogg, Nancy

doi:10.1074/jbc.m112.434621

Cited by 37 publications

(38 citation statements)

References 53 publications

(77 reference statements)

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“…54 Moreover, the PH domain of Kindlin-3 is essential for LFA-1-mediated regulation of lymphocyte adhesion and migration. 55 The intermediate affinity conformation of LFA-1 requires Talin-1, whereas further conformational changes associated with the high-affinity state are Kindlin-3 dependent. 54 Further work will help delineate how different PIP 3 -binding proteins co-ordinate the regulation of LFA-1 affinity and avidity.…”

Section: Discussionmentioning

confidence: 99%

PI3Kδ promotes CD4⁺ T‐cell interactions with antigen‐presenting cells by increasing LFA‐1 binding to ICAM‐1

Garçon

Okkenhaug

2016

Immunol Cell Biol

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Activation of T lymphocytes by peptide/major histocompatibility complex on antigen-presenting cells (APCs) involves dynamic contacts between the two cells, during which T cells undergo marked morphological changes. These interactions are facilitated by integrins. Activation of the T cells increases the binding of the integrin lymphocyte function-associated antigen 1 (LFA-1) expressed by T cells to intercellular adhesion molecule (ICAM)-1 and ICAM-2 expressed by APCs. The signalling pathways that control integrin affinities are incompletely defined. The phosphoinositide 3-kinases (PI3Ks) generate second-messenger signalling molecules that control cell growth, proliferation, differentiation and trafficking. Here we show that in T cells, PI3Kδ attenuates the activation of Rac1, but sustains the activation of Rap1. Consequently, PI3Kδ increases LFA-1-dependent adhesion to form stable conjugates with APCs. Increased Rap1 activity and LFA-1 adhesion were only in part mediated by the downstream kinase Akt, suggesting the involvement of additional phosphatidylinositol(3,4,5)P3-binding proteins. These results establish a link between PI3K activity, cytoskeletal changes and integrin binding and help explain the impaired T-cell-dependent immune responses in PI3Kδ-deficient mice.

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Section: Discussionmentioning

confidence: 99%

PI3Kδ promotes CD4⁺ T‐cell interactions with antigen‐presenting cells by increasing LFA‐1 binding to ICAM‐1

Garçon

Okkenhaug

2016

Immunol Cell Biol

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“…Alternatively, kindlins can recruit migfilin [43] and integrin-linked kinase (ILK) [12] to occupied integrins, thereby enabling the further recruitment of actin-binding proteins such as filamins, PINCHs and parvins [52] that could promote cooperative integrin clustering. Kindlins can also bind to polyphosphoinositides [53-55], thereby localizing integrins in membrane domains that might favor clustering. The present work will enable further studies to evaluate the precise roles of kindlin-binding proteins and phospholipids in the capacity of kindlins to increase multivalent ligand binding to and clustering of integrins.…”

Section: Discussionmentioning

confidence: 99%

The Mechanism of Kindlin-Mediated Activation of Integrin αIIbβ3

et al. 2013

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Increased ligand binding to cellular integrins (“activation”) plays important roles in processes such as development, cell migration, extracellular matrix assembly, tumor metastasis and hemostasis and thrombosis[1-5]. Integrin activation encompasses both increased integrin monomer affinity and increased receptor clustering[6] and depends on integrin-talin interactions[5]. Loss of kindlins results in reduced activation of integrins[7-13]. Kindlins might promote talin binding to integrins through a cooperative mechanism[5, 14-16]; however, kindlins do not increase talin association with integrins[17]. Here we report that, unlike talin head domain (THD), kindlin-3 caused little effect on the affinity of purified monomeric αIIbβ3, and it didn’t enhance activation by THD. Furthermore, studies with ligands of varying valency showed that kindlins primarily increased cellular αIIbβ3 avidity rather than monomer affinity. In platelets or nucleated cells, loss of kindlins markedly reduced αIIbβ3 binding to multivalent but not monovalent ligands. Finally, silencing of kindlins reduced the clustering of ligand-occupied αIIbβ3 as revealed by total internal reflection fluorescence (TIRF) and electron microscopy. Thus, in contrast to talins, kindlins have little primary effect on integrin αIIbβ3 affinity for monovalent ligands and increase multivalent ligand binding by promoting the clustering of talin-activated integrins.

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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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The Kindlin 3 Pleckstrin Homology Domain Has an Essential Role in Lymphocyte Function-associated Antigen 1 (LFA-1) Integrin-mediated B Cell Adhesion and Migration

Cited by 37 publications

References 53 publications

PI3Kδ promotes CD4⁺ T‐cell interactions with antigen‐presenting cells by increasing LFA‐1 binding to ICAM‐1

PI3Kδ promotes CD4⁺ T‐cell interactions with antigen‐presenting cells by increasing LFA‐1 binding to ICAM‐1

The Mechanism of Kindlin-Mediated Activation of Integrin αIIbβ3

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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The Kindlin 3 Pleckstrin Homology Domain Has an Essential Role in Lymphocyte Function-associated Antigen 1 (LFA-1) Integrin-mediated B Cell Adhesion and Migration

Cited by 37 publications

References 53 publications

PI3Kδ promotes CD4+ T‐cell interactions with antigen‐presenting cells by increasing LFA‐1 binding to ICAM‐1

PI3Kδ promotes CD4+ T‐cell interactions with antigen‐presenting cells by increasing LFA‐1 binding to ICAM‐1

The Mechanism of Kindlin-Mediated Activation of Integrin αIIbβ3

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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PI3Kδ promotes CD4⁺ T‐cell interactions with antigen‐presenting cells by increasing LFA‐1 binding to ICAM‐1

PI3Kδ promotes CD4⁺ T‐cell interactions with antigen‐presenting cells by increasing LFA‐1 binding to ICAM‐1