LFA-1 Affinity Regulation Is Necessary for the Activation and Proliferation of Naive T Cells

Wang, Yan; Li, Dan; Nurieva, Roza; Yang, Jenq-Lin; Şen, Mehmet; Carreño, Roberto; Lu, Sijie; McIntyre, Bradley W.; Molldrem, Jeffrey J.; Legge, Glen B.; Ma, Qing

doi:10.1074/jbc.m807207200

Cited by 46 publications

(40 citation statements)

References 60 publications

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“…As expected, we show here that LFA-1 antagonists also alter the DC-mediated proliferation of resting CD4 ϩ T cells in the presence of LPS and SEE. These results are consistent with other previously reported results showing that statin-derived compounds and XVA143 impair T-cell and NK cell activation as well as proliferation through an inhibition of LFA-1-mediated adhesion (64,65).…”

Section: Discussionsupporting

confidence: 83%

LFA-1 Antagonists as Agents Limiting Human Immunodeficiency Virus Type 1 Infection and Transmission and Potentiating the Effect of the Fusion Inhibitor T-20

Tardif

Gilbert

Thibault

et al. 2009

Antimicrob Agents Chemother

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Adhesion molecules are known to play major roles in the initiation and stabilization of cell-to-cell contacts during the immunological response. Human immunodeficiency virus type 1 (HIV-1) exploits those interactions to facilitate infection and propagation processes. The primary objective of the present study was to investigate the ability of antagonists specific for lymphocyte function-associated antigen 1 (LFA-1) to diminish HIV-1 infection and transmission. We demonstrate here that LFA-1 antagonists can significantly reduce HIV-1 replication in primary human cells and virus propagation by affecting cell-to-cell interactions. Moreover, the inhibition of LFA-1-mediated adhesion events also potentiates the antiviral efficacy of the peptide fusion inhibitor T-20. Altogether, our data suggest that LFA-1 antagonists represent promising antiviral agents. Antiadhesion therapy could be considered a complementary strategy targeting cellular functions essential for HIV-1 spreading and against which the combined therapy currently used displays a limited efficacy.

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Section: Discussionsupporting

confidence: 83%

LFA-1 Antagonists as Agents Limiting Human Immunodeficiency Virus Type 1 Infection and Transmission and Potentiating the Effect of the Fusion Inhibitor T-20

Tardif

Gilbert

Thibault

et al. 2009

Antimicrob Agents Chemother

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“…Additionally, we showed that cathepsin X promotes proliferation of T cells [38]. This is consistent with the study of Wang et al demonstrating that LFA-1 affinity regulation is crucial for the activation and proliferation of naïve T cells [39]. Thus, posttranslational modification of LFA-1 by cathepsin X constitutes a novel mechanism for highly dynamic integrin regulation with a significant impact on the function of T cells.…”

supporting

confidence: 79%

Cathepsin X cleaves the β2 cytoplasmic tail of LFA‐1 inducing the intermediate affinity form of LFA‐1 and α‐actinin‐1 binding

et al. 2009

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The motility of T cells depends on the dynamic spatial regulation of integrin-mediated adhesion and de-adhesion. Cathepsin X, a cysteine protease, has been shown to regulate T-cell migration by interaction with lymphocyte function associated antigen-1 (LFA-1). LFA-1 adhesion to the ICAM-1 is controlled by the association of actin-binding proteins with the cytoplasmic tail of the b 2 chain of LFA-1. Cleavage by cathepsin X of the amino acid residues S 769 , E 768 and A 767 from the C-terminal of the b 2 cytoplasmic tail of LFA-1 is shown to promote binding of the actin-binding protein a-actinin-1. Furthermore, cathepsin X overexpression reduced LFA-1 clustering and induced an intermediate affinity LFA-1 conformation that is known to associate with a-actinin-1. Increased levels of intermediate affinity LFA-1 resulted in augmented cell spreading due to reduced attachment of T cells to the ICAM-1-coated surface. Gradual cleavage of LFA-1 by cathepsin X enables the transition between intermediate and high affinity LFA-1, an event that is crucial for effective T-cell migration.Key words: a-Actinin-1 . b 2 Cytoplasmic tail . Cathepsin X . LFA-1 affinity . T-cell migration IntroductionIntegrins are a large family of a/b heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix adhesion and transduce signals bi-directionally across the plasma membrane. Lymphocyte function associated antigen-1 (LFA-1, a L b 2 , CD11a/CD18) belongs to the b 2 integrin subfamily and is constitutively expressed on all leukocytes. LFA-1 undergoes a dramatic conformational change that involves affinity regulation and cell surface clustering (valency regulation) during lymphocyte activation, which greatly increases the binding avidity (affinity1valency) for ligands such as ICAM-1, -2 and -3 [1, 2].LFA-1 can take up three conformations, a bent form and two extended forms. The bent form is inactive, whereas the extended forms, closed and open, exhibit intermediate and high affinities, respectively, for ICAM-1, depending on the angle between the hybrid and b-like I domains [3,4]. The extended conformations are recognized by mAb KIM 127 that binds to the epitope on the second EGF-like domain of the b 2 subunit, which is exposed when LFA-1 converts from the bent to the extended form [5,6]. Another antibody, mAb 24, recognizes solely the open, highaffinity conformation of LFA-1 [7].LFA-1 functions either by binding ligands through a process known as outside-in signaling or by binding cytoskeleton components for inside-out signaling. Although the a L and b 2 cytoplasmic tails of LFA-1 are relatively short, they play a pivotal role in these bi-directional signaling processes. For example, truncation of the b 2 cytoplasmic tail eliminates LFA-1 binding to 3 [15] that are the final effectors of inside-out signaling pathways. T-cell migration is a cyclic process that includes alternating integrin-mediated cell adhesion and de-adhesion, associated with regular activation and de-activation of integrins [16,17]. Accumulating...

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“…Specifically, LFA-1 is a costimulatory molecule mediating T cell proliferation and cytotoxicity (30,31). We demonstrated the affinity changes in the I-domain of LFA-1 during mouse T cell activation (17). However, little is known on the role of high affinity LFA-1 in human T cell function, although Efalizumab has been used in the clinic to target the I-domain of LFA-1 in inflammatory responses (18 -22).…”

Section: Discussionmentioning

confidence: 99%

“…By introducing disulfide bonds into the I-domain, LFA-1 can be locked in either the open or the closed conformation, which represents the HA (K287C/K297C) or LA (K287C/K294C) state, respectively (13)(14)(15). We identified antibodies that are sensitive to the affinity changes in the I-domain of mouse LFA-1 and showed that the activation-dependent epitopes were exposed upon mouse T cell activation (17). Taken together, these data demonstrated that the I-domain of LFA-1 changes to the high affinity state upon leukocyte activation.…”

mentioning

confidence: 99%

2E8 Binds to the High Affinity I-domain in a Metal Ion-dependent Manner

Carreño¹,

Brown²,

Li³

et al. 2010

Journal of Biological Chemistry

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The activation of leukocyte function-associated antigen-1 (LFA-1) plays a critical role in regulating immune responses. The metal ion-dependent adhesion site on the I-domain of LFA-1 ␣ L subunit is the key recognition site for ligand binding. Upon activation, conformation changes in the I-domain can lead LFA-1 from the low affinity state to the high affinity (HA) state. Using the purified HA I-domain locked by disulfide bonds for immunization, we developed an mAb, 2E8, that specifically binds to cells expressing the HA LFA-1. The surface plasmon resonance analysis has shown that 2E8 only binds to the HA I-domain and that the dissociation constant (K D ) for HA I-domain is 197 nM. The binding of 2E8 to the HA I-domain is metal ion-dependent, and the affinity decreased as Mn 2؉ was replaced sequentially by Mg 2؉ and Ca 2؉ . Surface plasmon resonance analysis demonstrates that 2E8 inhibits the interaction of HA I-domain and ICAM-1. Furthermore, we found that 2E8 can detect activated LFA-1 on both JY and Jurkat cells using flow cytometry and parallel plate adhesion assay. In addition, 2E8 inhibits JY cell adhesion to human umbilical vein endothelial cells and homotypic aggregation. 2E8 treatment reduces the proliferation of both human CD4 ؉ and CD8 ؉ T cells upon OKT3 stimulation without the impairment of their cytolytic function. Taken together, these data demonstrate that 2E8 is specific for the high affinity form of LFA-1 and that 2E8 inhibits LFA-1/ICAM-1 interactions. As a novel activation-specific monoclonal antibody, 2E8 is a potentially useful reagent for blocking high affinity LFA-1 and modulating T cell activation in research and therapeutics.Leukocyte function-associated antigen-1 (LFA-1, 3 ␣ L ␤ 2 integrin, CD11a/CD18) belongs to the ␤ 2 subclass of integrins and is important for leukocyte adhesion and T cell activation (1, 2). The ligands for LFA-1 are intercellular adhesion molecule-1 (ICAM-1), ICAM-2, and ICAM-3, which are members of the Ig superfamily (1). Although LFA-1 is constitutively expressed on the surface of leukocytes in an inactive state, binding to its ligands requires cellular activation involving both affinity (conformational change within the molecule) and avidity (receptor clustering) enhancement (3-5). The regulation of LFA-1 activation plays a critical role during inflammatory and immune responses in mice and humans (6 -9).The ␣ L subunit of LFA-1 has two prominent structural features, an inserted-domain (I-domain) of about 200 amino acid residues and three EF hand-like repeats containing putative divalent cation binding sites (1). The I-domain of the LFA-1 ␣ L subunit is the ligand binding site and changes conformation upon activation (10). The changes in the I-domain from the low affinity state to the high affinity state lead to an increased affinity for ligand binding (11)(12)(13)(14)(15). The key recognition site for ligand binding is at the metal ion-dependent adhesion site (MIDAS) on the I-domain of the LFA-1 ␣ L subunit (1, 2). Constitutively expressed on the surface of leukoc...

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LFA-1 Affinity Regulation Is Necessary for the Activation and Proliferation of Naive T Cells

Cited by 46 publications

References 60 publications

LFA-1 Antagonists as Agents Limiting Human Immunodeficiency Virus Type 1 Infection and Transmission and Potentiating the Effect of the Fusion Inhibitor T-20

LFA-1 Antagonists as Agents Limiting Human Immunodeficiency Virus Type 1 Infection and Transmission and Potentiating the Effect of the Fusion Inhibitor T-20

Cathepsin X cleaves the β2 cytoplasmic tail of LFA‐1 inducing the intermediate affinity form of LFA‐1 and α‐actinin‐1 binding

2E8 Binds to the High Affinity I-domain in a Metal Ion-dependent Manner

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