Phospholipase D1 Regulates Lymphocyte Adhesion via Upregulation of Rap1 at the Plasma Membrane

Mor, Adam; Wynne, Joseph; Ahearn, Ian M.; Dustin, Michael L.; Du, Guangwei; Philips, Mark R.

doi:10.1128/mcb.00366-09

Cited by 36 publications

(50 citation statements)

References 42 publications

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“…pcDNA-Rap1 and GFP-RBD-RalGDS constructs were previously described (6). The modified CAPRI constructs were subcloned from GFP-CAPRI (gift from Dr. Peter Lockyer, University of Bristol, Bristol, U.K.) by the use of nested primers.…”

Section: Dna Constructsmentioning

confidence: 99%

“…Activated Rap1 was detected by the GST pull-down assay, as previously described (6). Primary murine T cells were stimulated with immobilized anti-CD3 and/or anti-CD28 Abs as indicated for 5 min prior to cell lysis.…”

Section: Rap1 Activation Assaymentioning

confidence: 99%

“…The integrin LFA-1 is critical for T cell interactions with APCs. LFA-1 affinity for its counter-ligand, ICAM-1, is regulated by Rap1, a small GTPase that cycles between active (GTP-bound) and inactive (GDP-bound) conformations (6). As is true for all small GTPases, Rap1 activation is brokered by guanine nucleotide exchange factors that induce Rap1 to release GDP in favor of GTP binding.…”

mentioning

confidence: 99%

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CD28 Inhibits T Cell Adhesion by Recruiting CAPRI to the Plasma Membrane

Strazza

Azoulay-Alfaguter

Dun

et al. 2015

The Journal of Immunology

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CD28 is a coreceptor expressed on T lymphocytes. Signaling downstream of CD28 promotes multiple T cell functions such as proliferation, survival, and cytokine secretion. Adhesion to APCs is another function of T cells; however, little is known with regard to the role of CD28 in this process. Our previous studies have shown that CD28 inhibits T cell adhesion, but the underlying mechanism that mediates this process remains unknown. In the present study we discovered that signaling downstream of CD28 resulted in inhibition of Rap1 activity and decreased LFA-1–mediated adhesion. We showed that this was regulated by the recruitment of calcium-promoted Ras inactivator (CAPRI), a GTPase-activating protein, to the plasma membrane downstream of CD28 signaling. CAPRI trafficking to the plasma membrane was secondary to calcium influx and was mediated by its C2A and C2B domains. We conclude that CD28 inhibits Rap1-mediated adhesion by recruiting the protein CAPRI to the plasma membrane.

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Section: Dna Constructsmentioning

confidence: 99%

Section: Rap1 Activation Assaymentioning

confidence: 99%

mentioning

confidence: 99%

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CD28 Inhibits T Cell Adhesion by Recruiting CAPRI to the Plasma Membrane

Strazza

Azoulay-Alfaguter

Dun

et al. 2015

The Journal of Immunology

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“…There are two isoforms of PLD (1 and 2); both are found in the plasma membrane and in endosomes (41,42). Because translocation of endocytic vesicles to the plasma membrane depends on PLD1 (20,43), and because failure to activate PLD1 is a feature of anergy (36), we compared CXCL12-induced PLD activation in chemokineresponsive and chemokine-unresponsive CLL samples (Fig. 5A).…”

Section: Activation Of Pld and Arf1 Is Defective In Chemokine-unrespomentioning

confidence: 99%

“…As a third explanation, refractoriness of Rap1 to activation by GEFs could potentially arise through defective endosomal recycling. Thus, the chemokine-induced activation of Rap1 in T cells has been shown to require the phospholipase D (PLD)1-dependent recycling of endosomes containing Rap1 to the plasma membrane where Rap1 GEFs are located (19,20). According to this model, Rap1 would essentially be constitutively uncoupled from its activator GEFs.…”

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confidence: 99%

Chemokine Unresponsiveness of Chronic Lymphocytic Leukemia Cells Results from Impaired Endosomal Recycling of Rap1 and Is Associated with a Distinctive Type of Immunological Anergy

Pye

Rubio

Pusch

et al. 2013

The Journal of Immunology

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Trafficking of malignant lymphocytes is fundamental to the biology of chronic lymphocytic leukemia (CLL). Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and αLβ2 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed αLβ2 activation and TEM unless α4β1 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Furthermore, failure of chemokine-induced Rap1 translocation/GTP loading was associated with a specific pattern of cellular IgD distribution resembling that observed in normal B cells anergized by DNA-based Ags. Anergic features and chemokine unresponsiveness could be simultaneously reversed by culturing CLL cells ex vivo, suggesting that these two features are coupled and driven by stimuli present in the in vivo microenvironment. Finally, we show that failure of Rap1 translocation/GTP loading is linked to defective activation of phospholipase D1 and its upstream activator Arf1. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1/phospholipase D1–mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags.

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Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

Laufer

Legler

2018

Journal of Leukocyte Biology

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Chemokines and their receptors coordinate the positioning of leukocytes, and lymphocytes in particular, in space and time. Discrete lymphocyte subsets, depending on their activation and differentiation status, express various sets of chemokine receptors to be recruited to distinct tissues. Thus, the network of chemokines and their receptors ensures the correct localization of specialized lymphocyte subsets within the appropriate microenvironment enabling them to search for cognate antigens, to become activated, and to fulfill their effector functions. The chemokine system therefore is vital for the initiation as well as the regulation of immune responses to protect the body from pathogens while maintaining tolerance towards self. Besides the well investigated function of orchestrating directed cell migration, chemokines additionally act on lymphocytes in multiple ways to shape immune responses. In this review, we highlight and discuss the role of chemokines and chemokine receptors in controlling cell-to-cell contacts required for lymphocyte arrest on endothelial cells and immunological synapse formation, in lymphocyte priming and differentiation, survival, as well as in modulating effector functions.

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Phospholipase D1 Regulates Lymphocyte Adhesion via Upregulation of Rap1 at the Plasma Membrane

Cited by 36 publications

References 42 publications

CD28 Inhibits T Cell Adhesion by Recruiting CAPRI to the Plasma Membrane

CD28 Inhibits T Cell Adhesion by Recruiting CAPRI to the Plasma Membrane

Chemokine Unresponsiveness of Chronic Lymphocytic Leukemia Cells Results from Impaired Endosomal Recycling of Rap1 and Is Associated with a Distinctive Type of Immunological Anergy

Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

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