The Spontaneously Adhesive Leukocyte Function-associated Antigen-1 (LFA-1) Integrin in Effector T Cells Mediates Rapid Actin- and Calmodulin-dependent Adhesion Strengthening to Ligand under Shear Flow

Lek, Hwee San; Morrison, Vicky L.; Conneely, M. J.; Campbell, Paul A.; McGloin, David; Kliche, Stefanie; Watts, Colin; Prescott, Alan R.; Fagerholm, Susanna C.

doi:10.1074/jbc.m112.430918

Cited by 25 publications

(34 citation statements)

References 29 publications

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“…Under static conditions, which mimic T-cell adhesion in tissues where shear flow is absent, b2 TTT/AAA integrin knock-in T cells showed reduced adhesion to ligand ( Figure 3A). More importantly, under conditions of shear flow (mimicking conditions in blood vessels 20 ), SDF-1-induced adhesion of naïve CD4 T cells to ICAM-1 was almost completely abolished by the TTT/AAA mutation ( Figure 3B). However, LFA-1 surface expression in knock-in naïve T cells was lower than in WT cells ( Figure 3C top).…”

Section: B2mentioning

confidence: 99%

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The β2 integrin–kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo

Morrison

MacPherson

Savinko

et al. 2013

Blood

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Key Points• TTT-motif in beta2-integrin binds kindlin-3.• Mutation of TTT-motif affects T-cell homing not activation.Kindlin-3 is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, which is characterized by deficient integrin-mediated adhesion of leukocytes and platelets. However, the specific roles of kindlin-3-b2-integrin interactions in T-cell adhesion and homing and immune responses in vivo remain unclear. Here, we show that the TTT motif in b2 integrins controls kindlin-3 binding. Mutation of the kindlin-3 binding site in b2 integrins caused a loss of firm adhesion of T cells under both static and shear flow conditions and a reduction of T-cell homing to lymph nodes in vivo. However, atomic force microscopy studies of integrin-ligand bonds revealed that initial ligand binding could still occur, and 2-dimensional T-cell migration was reduced but not abolished by the TTT/AAA mutation in the b2 integrin. Importantly, dendritic cell-mediated T-cell activation in vivo was normal in TTT/AAA b2 integrin knock-in mice. Our results reveal a selective role of the kindlin-3-integrin association for lymphocyte functions in vivo; the integrin-kindlin-3 interaction is particularly important in adhesion strengthening under shear flow, and for T-cell homing to lymph nodes, but dispensable for T cell activation which occurs in a

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Section: B2mentioning

confidence: 99%

“…20 In brief, Arrow TL2 cantilevers (NanoSensors) were functionalized with 0.5 mg/mL purified anti-CD43 (eBioscience). Cantilevers were calibrated for sensitivity and spring constants before experiments.…”

Section: Atomic Force Microscopymentioning

confidence: 99%

The β2 integrin–kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo

Morrison

MacPherson

Savinko

et al. 2013

Blood

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“…The a E (CD103)b 7 integrin, hereafter referred to as CD103, plays a crucial role in TCR-mediated cytokine secretion and cytotoxic activity toward epithelial tumors by interacting with its ligand, epithelial cell marker E-cadherin, on target cells (8,9). This integrin is essential in controlling CD8…”

Section: Introductionmentioning

confidence: 99%

“…However, T-cell stimulation through T-cell receptor (TCR) or chemokine receptors triggers an "inside-out" signal that results in LFA-1 activation by inducing integrin-extended conformation and clustering, thereby increasing its affinity for its ligands (5). Firm adhesion of LFA-1 to ICAM-1 (CD54) initiates an "outside-in" signal that has costimulatory functions in TCR signaling, thus contributing to T-cell stimulation, spreading, and cytotoxicity (6,7).…”

Section: Introductionmentioning

confidence: 99%

TGFβ Signaling Intersects with CD103 Integrin Signaling to Promote T-Lymphocyte Accumulation and Antitumor Activity in the Lung Tumor Microenvironment

et al. 2016

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Homing of CD8þ T lymphocytes to the tumor microenvironment is an important step for mounting a robust antitumor immune response. TGFb is responsible for CD103 (a E b 7 ) integrin induction in activated intraepithelial CD8 þ T lymphocytes. However, the interplay between TGFb and CD103 and their contribution to T-cell infiltration and antitumor activity remain unknown. Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Moreover, TGFb enhanced CD103-dependent Tcell adhesion and signaling, whereas it inhibited leukocyte function-associated antigen (LFA)-1 (a L b 2 ) integrin expression and LFA-1-mediated T-lymphocyte functions. Mechanistic investigations revealed that TGFb bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrinlinked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation, thereby initiating integrin insideout signaling. Collectively, our findings suggest that the abundance of TGFb in the tumor microenvironment may in fact engage with integrin signaling pathways to promote T-lymphocyte antitumor functions, with potential implications for T-cell-based immunotherapies for cancer. Cancer Res; 76(7); 1757-69. Ó2016 AACR.

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“…The activation and redistribution of F-actin is regulated by calcium signaling, adhesion molecules [32,33] and actin-budling proteins. Fascin-1, an actin-budling protein that regulates F-actin, is solely expressed in mature DCs and is absent in other myeloid cells.…”

Section: Regulators Of F-actin In Dcsmentioning

confidence: 99%

Regulating DCs in Innate Immune Response and Infection by Cytoskeletal Proteins

Lin¹,

Wang²

2017

J immuno Biol

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Dendritic cells (DCs) are important antigen-presenting cells of innate immune system. Their main function is to take up antigen and present it to T-cells to active adaptive immune response. The cytoskeletal proteins of the DCs not only maintain the morphology of DCs, but also are associated with the maturation and function of DCs. Additionally, rearrangement of cytoskeletal proteins is associated with viral infection in DCs. Regulating the specific cytoskeletal proteins of DCs would be a potential therapeutic strategy for preventing viral infection. Thus, the role of cytoskeletal proteins of DCs in immune response and viral infections were reviewed.

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The Spontaneously Adhesive Leukocyte Function-associated Antigen-1 (LFA-1) Integrin in Effector T Cells Mediates Rapid Actin- and Calmodulin-dependent Adhesion Strengthening to Ligand under Shear Flow

Cited by 25 publications

References 29 publications

The β2 integrin–kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo

The β2 integrin–kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo

TGFβ Signaling Intersects with CD103 Integrin Signaling to Promote T-Lymphocyte Accumulation and Antitumor Activity in the Lung Tumor Microenvironment

Regulating DCs in Innate Immune Response and Infection by Cytoskeletal Proteins

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