CTLA-4 Regulation of T Cell Function via RAP-1-Mediated Adhesion

Schneider, Helga; Valk, Elke; Dias, Silvy da Rocha; Wei, Bin; Rudd, Christopher E.

doi:10.1007/0-387-34132-3_9

Cited by 7 publications

(10 citation statements)

References 45 publications

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“…Finally, as the work by Schneider et al evaluating the co-inhibitory receptor, such as CTLA-4 [20] suggested that inter-cellular adhesion molecules such as the β-integrins may also be effected by the increased expression of co-inhibitory molecules like PD-1 [22]. Using immune-staining co-localization by confocal imaging we attempted to determine the extent to which PD-1 antigen/receptor expression was associated/interacts with a member of the integrin family, CD11b.…”

Section: Resultsmentioning

confidence: 99%

“…Several studies looking at co-inhibitory receptors, such as cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) [20] have suggested that members of this family, which are related to PD-1 [21], may have an impact on motility/migratory capacity of T-lymphocytes. Furthermore, such effects on lymphocyte migration/motility may involve not only classical immune-receptor tyrosine inhibitory motif (ITIM) recruitment/activation of the phosphatases SHP-1/-2 [21], but signaling through Ras related protein 1 (RAP1) also effects cell adhesion molecules such as integrins [22]. However, the contribution of such co-inhibitors to direct/ indirect regulation of phagocyte functions such as, phagocytosis and migration, as well as how their actions might be mediated in monocytes/macrophages, are not well understood.…”

Section: Introductionmentioning

confidence: 99%

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Sepsis-Induced Potentiation of Peritoneal Macrophage Migration Is Mitigated by Programmed Cell Death Receptor-1 Gene Deficiency

et al. 2013

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The effect of programmed cell death receptor-1 (PD-1) on phagocyte function has not been extensively described. Here we report that experimental mouse sepsis, cecal ligation and puncture (CLP), induced a marked increase in peritoneal macrophage random migration, motility and cell spread, but these changes were lost in the absence of PD-1. Alternatively, phagocytic activity was inversely affected. In vitro cell culture imaging studies, with the macrophage cell line J774, documented that blocking PD-1 with antibody led to aggregation of the cytoskeletal proteins α-actinin and F-actin. Further experiments looking at ex vivo peritoneal macrophages from mice illustrated that a similar pattern of α-actinin and F-actin was evident on cells from wild-type CLP mice but not PD-1-/- CLP mouse cells. We also observed that fMLP-induced migration by J774 cells was markedly attenuated using PD-1 blocking antibodies, a nonselective phosphatase inhibitor and a selective Ras-related protein 1 inhibitor. Finally, peritoneal macrophages derived from CLP as opposed to Sham mice demonstrated aspects of both cell surface co-localization with CD11b and internalization of PD-1 within vacuoles independent of CD11b staining. Together, we believe the data support a role for PD-1 in mediating aspects of innate macrophage immune dysfunction during sepsis, heretofore unappreciated.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sepsis-Induced Potentiation of Peritoneal Macrophage Migration Is Mitigated by Programmed Cell Death Receptor-1 Gene Deficiency

et al. 2013

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“…The constitutive expression by Tregs of CTLA-4, implicated in their suppressive phenotype, leads to downregulation of B7 molecules on APCs and induction of APC-expressed IDO, a metabolic enzyme that catabolizes tryptophan leading to starvation of T cells (10,11). CTLA-4 signaling has also been shown to be responsible for reversing the TCR-stop, effectively ending the process of activation by detachment of the immunological synapse and increased T-cell motility (12,13).…”

Section: Introductionmentioning

confidence: 99%

Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell–Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects

Fransen

Sluis

Ossendorp

et al. 2013

Clinical Cancer Research

176

144

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Purpose: Blockade of CTLA-4 by antibodies has potentiated antitumor T-cell responses in both preclinical models and clinical trials. However, treatment with CTLA-4 blocking antibodies is associated with autoimmune and inflammatory side effects. In this study, we propose a novel administration method for CTLA-4 blocking antibodies as monotherapy.Experimental Design: We use different preclinical mouse models of cancer to investigate the local administration of CTLA-4 blocking antibody and its effect on cancer progression and the antitumor T-cell response.Results: By injecting the antibodies in a subcutaneous slow-release delivery formulation in the tumor area, we show that an eight-fold lower dose of antibody is as effective in inducing tumor eradication as systemic delivery. A lower dose and slow release of the antibody results in thousand-fold decreased levels of antibody in the serum, reducing adverse events and the risk of autoimmunity. The main target and effector cells of the CTLA-4 blockade treatment in the studied tumor models are tumor-specific endogenous CD8 þ T cells that are capable of eradicating also distant tumors, whereas CD4 þ T cells do not play a prominent role in the antibody-mediated tumor eradication. Conclusions: Injecting CTLA-4 blocking antibody in a slow-release formulation close to the tumor is an effective way of activating the antitumor T-cell response. This administration method is associated with very low serum levels of antibody, which decreases the risk of treatment-induced side effects. These results call for exploration of a similar delivery principle in clinical settings.

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“…The same group examined the effect of CTLA-4 engagement on migration of preactivated mouse CTLA-4-deficient T-cells both in vitro and in vivo. Surprisingly, CTLA-4 triggering led to enhanced migration on ICAM-1-coated plates and short-lived adhesion to cognate APCs in vivo, suggesting that CTLA-4 engagement may prevent further interactions with APCs [37].…”

Section: Differential Regulation Of T-cell Migration By Cd28 and Ctla-4mentioning

confidence: 98%

Regulation of T-cell migration by co-stimulatory molecules

David

Marelli‐Berg

2007

Biochemical Society Transactions

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Migration of primed T-cells to the antigenic site is an essential event in the development of effective immunity. This process is tightly regulated in order to ensure efficient and specific responses. Most studies have focused on non-specific mediators of T-cell migration, including integrins and chemokines. However, recent studies have highlighted the key role of the T-cell receptor and co-stimulatory molecules in guiding T-cell access to antigenic tissue. Here, we review the experimental evidence for an essential contribution of co-stimulation-mediated molecular interactions regulating T-cell migration in the development of T-cell immunity and tolerance.

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CTLA-4 Regulation of T Cell Function via RAP-1-Mediated Adhesion

Cited by 7 publications

References 45 publications

Sepsis-Induced Potentiation of Peritoneal Macrophage Migration Is Mitigated by Programmed Cell Death Receptor-1 Gene Deficiency

Sepsis-Induced Potentiation of Peritoneal Macrophage Migration Is Mitigated by Programmed Cell Death Receptor-1 Gene Deficiency

Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell–Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects

Regulation of T-cell migration by co-stimulatory molecules

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