Affinage

ITGAL

Integrin alpha-L · UniProt P20701

Length
1170 aa
Mass
128.8 kDa
Annotated
2026-04-28
100 papers in source corpus 47 papers cited in narrative 47 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITGAL encodes the αL subunit of LFA-1 (αLβ2; CD11a/CD18), a leukocyte-restricted integrin that mediates cell adhesion, migration, immune synapse formation, and effector functions by binding intercellular adhesion molecules ICAM-1, ICAM-2, and ICAM-3 through its I domain (PMID:3340213, PMID:23775590). LFA-1 adhesive activity is regulated at two levels: affinity, controlled by divalent cations (Mg²⁺ activates; Ca²⁺ inhibits) and conformational transitions among inactive, intermediate, and high-affinity extended states (PMID:1346139, PMID:1703161), and avidity, governed by actin cytoskeleton–dependent nanoclustering requiring talin, L-plastin, and WASP, with the GFFKR cytoplasmic motif acting as an intrinsic deactivation switch whose deletion causes constitutive adhesion and impaired migration (PMID:10480895, PMID:15955836, PMID:29386139, PMID:25666810). Inside-out activation proceeds through TCR-, CD40-, or chemokine-triggered pathways involving Rap1, Lck, Ras–MAPK, and PI3K signaling, while outside-in signaling through the β2 tail engages JAB1/AP-1 and SRC-family kinases (PMID:10766246, PMID:9834054, PMID:11165259, PMID:29100055). Tissue-specific and disease-relevant expression is epigenetically controlled by RFX1-recruited DNMT1, HDAC1, and SUV39H1 at the ITGAL promoter, and promoter hypomethylation in systemic lupus erythematosus CD4⁺ T cells leads to pathological CD11a overexpression (PMID:20223637, PMID:21192791, PMID:12115234).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1988 High

    Identification of ICAM-1 as a direct LFA-1 ligand established the molecular basis of LFA-1-mediated intercellular adhesion, showing that this integrin uses a non-RGD mechanism.

    Evidence Reconstitution of purified ICAM-1 into artificial membranes with cell adhesion assays and cDNA cloning

    PMID:3340213

    Open questions at the time
    • ICAM-2 and ICAM-3 binding sites on αL not yet mapped
    • structural basis of LFA-1/ICAM-1 contact unknown
  2. 1991 High

    The discovery that LFA-1 exists in at least three conformational states (inactive, intermediate, high-affinity) and that TCR/PMA signaling triggers transitions between them established the concept of inside-out integrin activation in leukocytes.

    Evidence Conformational reporter mAbs (NKI-L16), Fab fragment studies, TCR/CD3 and PMA stimulation, and early talin co-capping experiments

    PMID:1703161 PMID:2150484

    Open questions at the time
    • molecular identity of intermediate vs. high-affinity structural differences unresolved
    • signaling intermediates between TCR and LFA-1 unknown
  3. 1992 High

    Demonstrating that Mn²⁺ directly induces high-affinity LFA-1 while Ca²⁺ maintains the inactive state resolved how divalent cation composition controls integrin function.

    Evidence Ion chelation with EGTA, Mn²⁺/Mg²⁺/Ca²⁺ titrations, mAb 24 conformational reporter, T cell adhesion to ICAM-1

    PMID:1346139

    Open questions at the time
    • cation coordination sites in the I domain not structurally defined
    • physiological relevance of Mn²⁺ unclear
  4. 1993 High

    Mapping the activation epitope to the I domain of CD11a localized the ligand-binding and regulatory center to a defined structural module, directing subsequent structural and pharmacological studies.

    Evidence mAb MEM-83 epitope mapped by in vitro–translated cDNA deletion series; Fab adhesion assays

    PMID:7680657

    Open questions at the time
    • atomic-resolution I domain structure not yet available
    • allosteric coupling between I domain and β-propeller unknown
  5. 1998 Medium

    Establishing that Ras–MAPK and PI3K pathways are both required for TCR-triggered LFA-1 activation identified the signaling cascades linking antigen recognition to integrin activation.

    Evidence Dominant-negative/constitutively active p21ras, MEK and PI3K inhibitors, ICAM-1 adhesion assays

    PMID:9834054

    Open questions at the time
    • direct phosphorylation targets on LFA-1 subunits not identified
    • relative contribution of Ras vs. Rap1 not resolved
  6. 1999 High

    Demonstrating that the GFFKR cytoplasmic motif constrains LFA-1 in an inactive state and that the actin cytoskeleton regulates avidity (clustering) independently of affinity separated two fundamental mechanisms of adhesion regulation.

    Evidence Cytoplasmic tail deletion mutants in K562 cells; soluble ICAM-1 affinity titration; cytochalasin D treatment

    PMID:10480895

    Open questions at the time
    • structural basis of GFFKR-mediated inhibition unknown
    • how actin drives clustering mechanistically not determined
  7. 1999 High

    The crystal structure of lovastatin bound to the I domain allosteric site (IDAS) provided the first atomic view of LFA-1 inhibition and validated the I domain as a druggable target.

    Evidence X-ray crystallography and NMR spectroscopy of lovastatin–I domain complex; functional binding assay

    PMID:10493852

    Open questions at the time
    • full-length αLβ2 ectodomain structure lacking
    • mechanism of allosteric transmission from IDAS to MIDAS not resolved
  8. 2000 High

    Discovery that JAB1 binds the β2 cytoplasmic tail and LFA-1 engagement promotes JAB1 nuclear translocation and AP-1 activation identified a direct outside-in transcriptional signaling axis.

    Evidence Yeast two-hybrid, co-immunoprecipitation, confocal co-localization, AP-1 reporter assay

    PMID:10766246

    Open questions at the time
    • physiological gene targets of JAB1/AP-1 downstream of LFA-1 not defined
    • whether RanBPM and JAB1 cooperate or compete for β2 binding unknown
  9. 2001 High

    Showing that Rap1 GTPase mediates PI3K-dependent LFA-1 activation placed Rap1 as a central inside-out signaling switch, complementing Ras–MAPK findings.

    Evidence CD98 cross-linking; PI3K inhibitors; retroviral overexpression of Rap1 GAP SPA-1; Rap1-GTP pull-down

    PMID:11165259

    Open questions at the time
    • direct Rap1 effector linking to talin or integrin tail unidentified
    • Rap1 vs. Rap2 roles in activation vs. recycling not separated
  10. 2002 High

    Identification of DNA methylation at non-CpG-island flanking sequences as a key epigenetic regulator of ITGAL expression, with hypomethylation in SLE T cells, linked integrin dysregulation to autoimmune disease.

    Evidence Bisulfite sequencing of lupus and control T cells; patch methylation of reporter constructs; 5-azacytidine treatment

    PMID:12036881 PMID:12115234

    Open questions at the time
    • transcription factor access changes caused by demethylation not characterized
    • whether methylation changes are cause or consequence of lupus not established
  11. 2002 High

    Demonstrating that Lck is required for proper CD11a/CD18 surface expression and maturation, beyond just signaling, revealed a biosynthetic role for SFKs in LFA-1 function.

    Evidence Lck-deficient Jurkat cells; Lck reconstitution; surface labeling showing unprocessed CD18; ICAM-1 adhesion assays

    PMID:12115650

    Open questions at the time
    • direct Lck phosphorylation site on β2 subunit or chaperone target not mapped
    • whether other SFKs compensate in primary T cells unknown
  12. 2004 High

    Identification of RhoH as a tonic inhibitor that keeps LFA-1 nonadhesive on resting lymphocytes revealed a GTPase-based brake mechanism complementing the GFFKR deactivation motif.

    Evidence RhoH-deficient Jurkat clone; RNAi in primary lymphocytes; reconstitution rescue; ICAM adhesion assays

    PMID:15300248

    Open questions at the time
    • downstream effectors of RhoH that restrain LFA-1 unknown
    • whether RhoH acts on affinity, avidity, or both not determined
  13. 2005 High

    Genetic knock-in deletion of GFFKR in mice proved that integrin deactivation, not just activation, is essential for T cell migration and immune function, establishing a requirement for adhesion cycling.

    Evidence GFFKR knock-in mouse; adhesion/de-adhesion assays; neutrophil recruitment; migration assays in vivo and in vitro

    PMID:15955836

    Open questions at the time
    • molecular mechanism by which GFFKR enforces deactivation (binding partner or structural constraint) unresolved
    • relative contributions in different leukocyte lineages not fully assessed
  14. 2005 High

    Demonstrating that talin is essential for both focal zone formation and TCR-triggered LFA-1 activation unified the concepts of affinity modulation and spatial clustering under a single cytoskeletal adaptor.

    Evidence Talin dominant-negative constructs and siRNA knockdown; live cell imaging on ICAM-1; T cell–APC conjugation assays

    PMID:15983060 PMID:17114441

    Open questions at the time
    • kindlin-3 contribution to talin-dependent activation not yet addressed
    • talin binding site on αL vs. β2 tail contributions unclear
  15. 2006 High

    Visualization of preformed LFA-1 nanoclusters on resting monocytes that dynamically merge into macroclusters upon contact established the nanocluster model of integrin avidity regulation.

    Evidence High-resolution fluorescence microscopy; live imaging of monocyte–T cell conjugates; talin co-localization

    PMID:16855029

    Open questions at the time
    • composition of nanocluster lipid/protein scaffold not defined
    • whether nanoclusters exist on all leukocyte types unknown
  16. 2010 High

    Identification of calpain 2 as mediating trailing-edge LFA-1 adhesion turnover during T cell migration completed the adhesion cycling model by defining the de-adhesion protease.

    Evidence siRNA knockdown; calpain inhibitors; live cell imaging; ORAI1-mutant patient T cells

    PMID:21152086

    Open questions at the time
    • calpain 2 cleavage site on LFA-1 or its adaptors not identified
    • relationship between calpain and GFFKR-mediated deactivation unclear
  17. 2010 High

    Characterization of RFX1-recruited DNMT1, HDAC1, and SUV39H1 at the ITGAL promoter provided a complete epigenetic silencing mechanism, and showed that RFX1 loss in SLE causes coordinate derepression.

    Evidence ChIP; co-immunoprecipitation of RFX1 with chromatin modifiers; gain/loss-of-function of RFX1; bisulfite sequencing

    PMID:20223637 PMID:21192791

    Open questions at the time
    • signals that downregulate RFX1 in SLE not identified
    • whether other integrin genes are co-regulated by RFX1 unknown
  18. 2015 High

    Showing that F-actin retrograde flow drives LFA-1 affinity maturation at the immunological synapse linked cytoskeletal force to conformational activation, unifying the mechanical and biochemical models of integrin regulation.

    Evidence F-actin inhibitor cocktails; TIRF and confocal microscopy with conformation-specific LFA-1 antibodies; ligand mobility assays

    PMID:25666810

    Open questions at the time
    • force magnitude required for conformational change not measured
    • relative contribution of induced fit vs. catch-bond mechanism unclear
  19. 2017 High

    Identification of extracellular ISG15 as a second ligand that signals through the αL I domain via SRC-family kinases expanded LFA-1 function beyond ICAM binding to cytokine-regulatory outside-in signaling.

    Evidence In vitro ISG15–I domain binding; CD11a-knockout splenocytes; SFK inhibition; NK cell IFN-γ release assay

    PMID:29100055

    Open questions at the time
    • ISG15 binding site relative to ICAM-1 site not structurally resolved
    • whether ISG15 competes with ICAM-1 for I domain binding unknown
  20. 2018 High

    Demonstrating that WASP organizes high-affinity LFA-1 nanoclusters at the lytic synapse and is required for cytotoxic killing connected actin nucleation machinery to nanoscale integrin patterning and effector function.

    Evidence Super-resolution microscopy; Wiskott-Aldrich syndrome patient CD8⁺ T cells; cytotoxicity assays

    PMID:29386139

    Open questions at the time
    • whether WASP acts directly on LFA-1 clusters or indirectly via cortical actin not distinguished
    • contribution of other actin nucleators (e.g., WAVE) not assessed
  21. 2022 High

    Establishing that extracellular Mg²⁺ is sensed through LFA-1 conformation on CD8⁺ T cells to enhance calcium flux, metabolic reprogramming, and cytotoxicity linked systemic ion homeostasis to adaptive immune function via integrin conformational sensing.

    Evidence LFA-1 conformation assays with Mg²⁺ titration; calcium flux; metabolic assays; immune synapse imaging; CAR T cell functional assays

    PMID:35051368

    Open questions at the time
    • whether Mg²⁺ sensing is unique to LFA-1 or shared by other β2 integrins not determined
    • in vivo relevance of physiological Mg²⁺ fluctuations for anti-tumor immunity unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length αLβ2 ectodomain structure capturing all three conformational states, the precise force thresholds for mechano-activation, direct identification of calpain cleavage targets in the LFA-1 adhesion complex, and the signals that downregulate RFX1 in autoimmunity.
  • no full-length αLβ2 cryo-EM structure in all three states
  • molecular basis of GFFKR-mediated deactivation not structurally resolved
  • in vivo force measurement on LFA-1 during migration not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 3
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 6 R-HSA-1500931 Cell-Cell communication 5 R-HSA-1474244 Extracellular matrix organization 2
Partners
COPS5ICAM1ICAM2ICAM3ISG15LPLRANBP9TLN1
Complex memberships
LFA-1 (αLβ2; CD11a/CD18)

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 ICAM-1 was identified as a direct adhesion ligand for LFA-1 (CD11a/CD18); purified ICAM-1 reconstituted into artificial membranes binds LFA-1+ cells, and ICAM-1 is homologous to NCAM but contains no RGD motifs. Reconstitution of purified ICAM-1 into artificial membranes; cell adhesion assay; cDNA cloning and sequence analysis Nature High 3340213
1992 Divalent cations regulate LFA-1 function: Mn2+ directly induces a high-affinity conformation of LFA-1 promoting ICAM-1 binding; Mg2+ supports activation when Ca2+ is removed; Ca2+ acts as a negative regulator maintaining LFA-1 in an inactive state. T cell adhesion assay to ICAM-1; mAb epitope mapping (mAb 24); EGTA/ion chelation experiments; flow cytometry The Journal of cell biology High 1346139
1991 LFA-1 activation is linked to a Ca2+-dependent epitope on the alpha subunit (recognized by mAb NKI-L16); three distinct conformational states of LFA-1 were proposed: inactive (NKI-L16−), intermediate (NKI-L16+), and active (NKI-L16+ with high-affinity ligand binding) induced by TCR/CD3 or PMA signaling. mAb-induced cell aggregation; Fab fragment studies; flow cytometry; Ca2+-dependent epitope characterization; PMA and TCR/CD3 stimulation The Journal of cell biology High 1703161
1993 A novel LFA-1 activation epitope (recognized by mAb MEM-83) was mapped to the I domain of the CD11a alpha subunit; binding of this epitope with Mg2+ directly induces T cell adhesion to ICAM-1, implicating the I domain in regulation of LFA-1 ligand binding. mAb screening panel; Fab fragment adhesion assay; in vitro-translated CD11a cDNA deletion series to map epitope; ICAM-1 binding assay The Journal of cell biology High 7680657
1999 Lovastatin binds to the I domain of the LFA-1 alpha chain (CD11a) and inhibits LFA-1 interaction with ICAM-1; X-ray crystallography and NMR revealed the atomic details of inhibitor binding to the I domain allosteric site (IDAS). X-ray crystallography; NMR spectroscopy; functional LFA-1/ICAM-1 binding assay Journal of molecular biology High 10493852
2000 The cytoplasmic domain of the LFA-1 beta2 subunit directly interacts with JAB1 (Jun activation domain-binding protein 1); LFA-1 engagement increases nuclear translocation of JAB1, leading to enhanced AP-1 (c-Jun) transcriptional activity. Yeast two-hybrid screen; co-immunoprecipitation; confocal co-localization; AP-1 reporter assay; nuclear fractionation Nature High 10766246
1999 The actin cytoskeleton regulates LFA-1 ligand binding through avidity (receptor clustering) rather than affinity changes; cytoplasmic tail deletion mutants of LFA-1 lacking KVGFFKR or beta2 tail show constitutive clustering and ICAM-1 binding without altered soluble ICAM-1 affinity. Cytoplasmic tail deletion mutants expressed in K562 cells; soluble ICAM-1 affinity titration; cytochalasin D treatment; flow cytometry for activation epitopes The Journal of biological chemistry High 10480895
2004 RanBPM was identified as a novel binding partner of the LFA-1 beta2 cytoplasmic domain; RanBPM co-localizes with LFA-1 at the cell membrane, is a phosphoprotein regulated by p38 kinase, and functionally synergizes with LFA-1 to activate AP-1-dependent transcription. Yeast two-hybrid screen; co-immunoprecipitation; co-localization microscopy; AP-1 reporter assay; phosphorylation analysis with kinase inhibitor The Journal of biological chemistry High 14722085
2005 High-affinity LFA-1 is restricted to a mid-cell 'focal zone' on migrating T lymphocytes; talin is essential for the stability and formation of this focal zone, and disruption of the talin-LFA-1 link reduces migration speed on ICAM-1. Live cell imaging on ICAM-1 substrates; confocal microscopy; talin disruption by dominant-negative constructs; migration speed measurement The Journal of cell biology High 15983060
2005 Talin1 is required for TCR-mediated activation of LFA-1, regulating both LFA-1 affinity and clustering; siRNA knockdown of talin1 impairs TCR-induced ICAM-1 adhesion and T cell–APC conjugation, and reduces LFA-1 polarization. siRNA knockdown; ICAM-1 adhesion assay; T cell–APC conjugation assay; flow cytometry for activation epitopes; confocal microscopy Journal of immunology High 17114441
2004 RhoH, a leukocyte-specific inhibitory Rho GTPase, is required to maintain LFA-1 in a nonadhesive state on resting lymphocytes; knockdown of RhoH causes constitutive LFA-1 adhesion to ICAM-1, -2, and -3, which is reversed by RhoH reconstitution. Identification of RhoH-deficient Jurkat clone; RNAi knockdown in peripheral blood lymphocytes; RhoH reconstitution; ICAM adhesion assay Nature immunology High 15300248
2005 Deletion of the GFFKR sequence in the LFA-1 alphaL cytoplasmic domain causes constitutive LFA-1 activation and impaired de-adhesion from ICAM-1, resulting in defective cell migration; LFA-1 deactivation (not just activation) is essential for T cell and neutrophil immune functions. Gene targeting (knock-in mutation) in mice; cell adhesion and de-adhesion assays; T cell activation assays; neutrophil recruitment assay; migration assay The Journal of experimental medicine High 15955836
2006 LFA-1 on monocytes is organized in well-defined nanoclusters (100–150 nm) containing primed (L16-epitope+) molecules linked to talin; upon contact formation these nanoclusters are dynamically recruited to the cell interface to form micrometer-sized macroclusters engaged in ligand binding. High-resolution fluorescence microscopy (PALM/STED-like); live imaging of MO-T cell conjugates; talin co-localization; functional adhesion assays Molecular biology of the cell High 16855029
2015 F-actin retrograde flow drives affinity maturation and spatial organization of LFA-1 conformational intermediates at the immunological synapse; F-actin forces maintain high-affinity LFA-1 conformation and promote ICAM-1 binding through a combination of induced fit and tension-based mechanisms. Inhibitor cocktail to arrest F-actin dynamics; TIRF and confocal microscopy with LFA-1 conformation-specific antibodies; ligand mobility assay The Journal of cell biology High 25666810
2017 Extracellular ISG15 signals cytokine (IFN-γ and IL-10) secretion through direct binding to the αI domain of CD11a (LFA-1); ISG15 engagement of LFA-1 activates SRC family kinases (SFKs), and SFK inhibition blocks cytokine secretion. NK-92 cell IFN-γ release assay; LFA-1 inhibition; CD11a-/- splenocytes; direct in vitro binding of ISG15 to αI domain; SFK inhibition Molecular cell High 29100055
2022 Extracellular magnesium is sensed via LFA-1, which requires Mg2+ to adopt its active conformation on CD8+ T cells; Mg-dependent LFA-1 activation augments calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and cytotoxicity. LFA-1 conformation assays with varying Mg2+ concentrations; calcium flux measurements; metabolic assays; immune synapse imaging; CAR T cell functional assays Cell High 35051368
2004 LFA-1 engagement alone (via ICAM-1 or ICAM-2-coated beads) is sufficient to polarize cytotoxic granules and initiate activation signals in NK cells, providing an early activation signal distinct from T cells which require co-receptor signals. ICAM-1 expressed on Drosophila insect cells; ICAM-1/ICAM-2-coated beads; NK cell cytotoxicity assay; inhibitory receptor blockade; granule polarization assay Journal of immunology High 15356110
2001 CD98 cross-linking activates LFA-1 to mediate ICAM-1-dependent adhesion in lymphocytes via PI3K-dependent activation of Rap1 GTPase; overexpression of the Rap1 GAP SPA-1 abolishes LFA-1/ICAM-1 adhesion. CD98 cross-linking; PI3K inhibitors; retroviral overexpression of SPA-1 (Rap1 GAP); ICAM-1 adhesion assay; Rap1-GTP pull-down FEBS letters High 11165259
1990 PMA treatment induces a direct or indirect association of talin with LFA-1 at the T helper cell surface, as shown by co-capping of talin with LFA-1 caps; this association correlates with increased LFA-1-dependent cell adhesion. LFA-1 antibody capping; double immunofluorescence microscopy; PMA stimulation; adhesion inhibition with anti-LFA-1 antibody Journal of molecular and cellular immunology Medium 2150484
2010 Calpain 2, a Ca2+-dependent cysteine protease most active at the trailing edge, mediates turnover of LFA-1 adhesions in migrating T lymphocytes; siRNA silencing or pharmacological inhibition of calpain causes elongation and shedding of LFA-1 clusters. siRNA knockdown; calpain inhibitors; live cell imaging; fluorescent calpain substrate (CMAC,t-BOC-Leu-Met); T cells from ORAI1-mutant patient PloS one High 21152086
2010 RFX1 recruits DNMT1 and HDAC1 to the CD11a (ITGAL) promoter to repress its expression; in SLE CD4+ T cells, reduced RFX1 expression causes DNA hypomethylation and histone H3 hyperacetylation at the ITGAL promoter, leading to CD11a overexpression. ChIP assay; co-immunoprecipitation; RFX1 overexpression/knockdown; RT-PCR; bisulfite sequencing Journal of autoimmunity High 20223637
2010 RFX1 recruits the histone methyltransferase SUV39H1 to the CD11a promoter in CD4+ T cells, maintaining H3K9 tri-methylation and thereby repressing CD11a expression; RFX1 downregulation in SLE reduces H3K9me3 at the ITGAL promoter. ChIP; co-immunoprecipitation of RFX1 and SUV39H1; RFX1 overexpression/knockdown; RT-PCR Arthritis research & therapy High 21192791
2002 DNA methylation of specific sequences flanking the ITGAL promoter (not CpG islands) suppresses ITGAL/CD11a expression; these sequences are hypomethylated in active lupus T cells and in T cells treated with methylation inhibitors, and patch methylation of the region in reporter constructs suppresses promoter function. Bisulfite sequencing; patch methylation of reporter constructs; luciferase promoter assay; 5-azacytidine and procainamide treatment Arthritis and rheumatism High 12115234
2002 DNA methylation and chromatin structure (DNase I sensitivity) contribute to tissue-specific ITGAL (CD11a) expression; the promoter is heavily methylated in fibroblasts (LFA-1 negative) but not T cells, and patch methylation of flanking regions suppresses promoter function. Bisulfite sequencing; DNase I sensitivity assay; patch methylation reporter assay; 5-azacytidine treatment of fibroblasts Blood High 12036881
2003 RUNX/AML and C/EBP factors regulate CD11a integrin expression through overlapping elements (MS7 sequence containing AML-110 and C/EBP-100 sites) in the CD11a promoter; in myeloid cells C/EBP factors bind in proliferating cells while RUNX3/AML-2 binds in differentiated cells, and AML-1/ETO inhibits CD11a promoter activity. ChIP; electrophoretic mobility shift assay (EMSA); promoter reporter assays; cell-lineage differentiation studies; AML-1/ETO transfection Blood High 12855590
2011 PLZF expression in NKT cells induces constitutive LFA-1–ICAM-1 interactions that mediate intravascular retention in the liver; antibody blocking experiments established that lifelong intravascular residence of NKT cells requires LFA-1/ICAM-1 interactions. Parabiotic mice; antibody blocking experiments; adoptive transfer; intravital microscopy; PLZF transgenic T cells The Journal of experimental medicine High 21624939
2008 Activated T cells recruit DC-secreted exosomes via high-affinity LFA-1 (not TCR specificity); inducing a high-affinity state of LFA-1 on resting T cells is sufficient to provoke exosome binding. Exosome binding assays; LFA-1 high-affinity induction; anti-LFA-1 blocking antibodies; T cell activation experiments Blood High 19064723
2007 CD8+ dendritic cells use LFA-1 (not Mac-1) to capture ICAM-1-bearing exosomes in vivo; CD8+ DCs express higher LFA-1 levels than CD8- DCs and are the main recipients of exosomes in lymphoid organs. In vivo exosome transfer experiments; blocking antibodies to LFA-1 and Mac-1; flow cytometry; LFA-1 and Mac-1 expression analysis on DC subsets Journal of immunology High 17641014
2010 Sustained LFA-1 clustering in the immunological synapse peripheral SMAC requires L-plastin (LPL) and calmodulin; siRNA knockdown of LPL abolishes LFA-1 and talin redistribution into the IS and inhibits T cell proliferation. siRNA knockdown of LPL; confocal microscopy; calmodulin inhibition; T cell–APC conjugate formation; proliferation assay European journal of immunology High 20683899
2018 WASP constrains high-affinity LFA-1 into dense nanoclusters in actin meshwork interstices and is required for assembly of a radial LFA-1 nanocluster belt at the lytic synapse; WASP deficiency reduces LFA-1 activation and impairs cytotoxic T cell killing. Super-resolution microscopy; confocal microscopy; Wiskott-Aldrich syndrome patient-derived CD8+ T cells (WASP null); lytic granule docking assay; cytotoxicity assay Cell reports High 29386139
2012 Rap2 GTPase is required for LFA-1 internalization and recycling during T lymphocyte migration; siRNA knockdown of Rap2 inhibits LFA-1 endocytosis and re-exposure, and causes intracellular accumulation of the extended-conformation form of LFA-1. siRNA knockdown; biotinylated membrane LFA-1 tracking; confocal microscopy of recycling vesicles; Rap1/Rap2 co-localization analysis Biology open Medium 23213397
2017 Cytoskeleton and ligand-bound LFA-1 integrins orient in the direction of retrograde actin flow during leukocyte migration, with β-subunit cytoplasm-binding tails tilted by applied intracellular force, supporting a model of integrin activation by cytoskeletal force. GFP insertion into integrin head; Rosetta structural modeling; fluorescence polarization microscopy on migrating cells Nature communications High 29229906
1998 The Ras–MAPK signaling pathway is required for TCR-activated LFA-1 adhesion; dominant-negative p21ras inhibits TCR-triggered ICAM-1 binding, while constitutively active p21ras enhances and sustains LFA-1 adhesion; PI3K and MEK inhibition are both needed for complete blockade. Dominant-negative and constitutively active p21ras expression; MEK inhibitor; PI3K inhibitor; ICAM-1 adhesion assay Journal of immunology Medium 9834054
2002 The Src-family kinase Lck is required for CD11a/CD18 (LFA-1) surface expression and activation in T cells; Lck-deficient Jurkat cells show reduced surface CD11a/CD18 with predominantly immature unprocessed CD18 not associated with CD11a; reconstitution of Lck restores adhesion. Lck-deficient Jurkat cells (JCaM1.6); Lck reconstitution; flow cytometry; cell surface labeling; ICAM-1 adhesion assay; Src kinase inhibitor PP2 European journal of immunology High 12115650
2004 Crystal structure and NMR analysis of an arylthio inhibitor bound to the LFA-1 I-domain allosteric site (IDAS) revealed atomic details of allosteric inhibition; ITC confirmed 18.3 nM binding affinity consistent with functional IC50. X-ray crystallography; 15N-1H HSQC NMR; isothermal titration calorimetry (ITC); DELFIA competition assay Biochemistry High 14992576
2006 E-selectin engagement induces partial activation of LFA-1 enabling LFA-1-dependent neutrophil rolling on ICAM-1; this process requires beta2 integrins (primarily LFA-1) and p38 MAPK signaling. Ex vivo flow chamber; blocking antibodies to LFA-1 and Mac-1; p38 MAPK inhibitor; co-immobilization of E-selectin and ICAM-1 Microcirculation High 16459323
2005 LFA-1 affinity state correlates with distinct adhesion functions in neutrophils: intermediate affinity supports rolling on ICAM-1, while high affinity is required for shear-resistant arrest and subsequent transmigration; high-affinity LFA-1 aligns along the uropod-pseudopod axis during transmigration. Parallel-plate flow chamber; allosteric I-domain inhibitor; conformation-specific antibodies; neutrophil transmigration assay on inflamed endothelium Blood High 16269618
2011 High-affinity LFA-1 engagement transmits mechanotransduced outside-in signals in neutrophils via cooperation with the calcium channel Orai1; low-affinity LFA-1 fails to induce calcium flux, F-actin polymerization, or directed migration, whereas high-affinity LFA-1 under shear provides orientation along a uropod-pseudopod axis requiring Orai1-dependent calcium flux. Vascular mimetic microfluidic channels; conformation-stabilizing allosteric antibodies; Orai1 inhibition; calcium flux imaging; F-actin imaging Journal of immunology High 21632714
2015 LFA-1 ligation (but not VLA-4 ligation) induces PI3K and ERK pathway activation and actin polymerization promoting upstream (against shear flow) T cell migration; Crk adaptor proteins and cCbl ubiquitin ligase are required downstream of LFA-1 for directed migration against shear flow. Primary mouse T cells; LFA-1/VLA-4 substrate comparison; PI3K and ERK inhibitors; Crk and cCbl knockout T cells; signaling phosphoproteomics Journal of cell science High 32907931
2007 Beta-sheets 1 and 2 of the CD11a beta-propeller domain are required for Aggregatibacter actinomycetemcomitans leukotoxin (Ltx) recognition and cytotoxicity; chimeric human/mouse CD11a constructs showed that the human N-terminal 128 amino acids containing these beta-sheets are sufficient for Ltx-mediated killing. Transfection of human, mouse, bovine alpha-L cDNAs into alpha-L-deficient cells; chimeric human/murine CD11a constructs; cytotoxicity assay Cellular microbiology High 17587330
2013 LFA-1 on macrophages (via alphaL/CD11a and beta2 subunits) recognizes ICAM3 on apoptotic neutrophils; siRNA silencing and antibody blockade of LFA-1 components in macrophages reduce phagocytosis of apoptotic neutrophils, and LFA-1 accumulates at phagocytic portals with ICAM3. siRNA knockdown; blocking antibodies; fluorescence co-localization at phagocytic portals; phagocytosis quantification assay Apoptosis Medium 23775590
2003 Membrane cholesterol depletion strongly inhibits LFA-1-mediated T cell adhesion; LFA-1 associates with cholesterol-rich lipid raft microdomains (distinct from GM1-rich rafts), and cross-linking of LFA-1 induces cocapping of cholesterol, suggesting raft association regulates LFA-1 clustering and function. Cholesterol depletion (MCD, filipin); cholesterol reconstitution; sucrose gradient fractionation with different detergents; LFA-1 cross-linking; adhesion assay Blood Medium 12637320
2015 CD9 tetraspanin directly associates with LFA-1 via its Large Extracellular Loop and inhibits LFA-1 adhesive function by altering its state of aggregation (not affinity); CD9 association negatively regulates LFA-1-dependent cytotoxic activity. Co-immunoprecipitation; proximity ligation assay; chemical crosslinking; pull-down with Large Extracellular Loop; LFA-1 aggregation assay; cytotoxicity assay Biochimica et biophysica acta Medium 26003300
2013 LFA-1 mediates prolonged lymph node residence by retaining T cells at the lymphatic exit points; LFA-1-deficient CD4+ T cells have significantly decreased dwell times in lymph nodes in an ICAM-1-dependent manner, and two-photon microscopy showed LFA-1+ T cells return to parenchyma more frequently from lymphatic sinuses. Intravital two-photon microscopy; LFA-1 knockout mice; ICAM-1 knockout hosts; dwell time measurements; egress kinetics The EMBO journal High 23443048
1991 LFA-1/ICAM-1 interactions are required for normal T lymphocyte development in the thymus; anti-LFA-1 or anti-ICAM-1 antibodies added to fetal thymic organ cultures impair generation of CD4+CD8+ double-positive thymocytes. Fetal thymic organ culture; antibody blocking; flow cytometry of thymocyte subsets Journal of immunology Medium 1680920
1991 CD40 signaling activates LFA-1 (CD11a/CD18)-mediated B cell homotypic adhesion; CD40 cross-linking requires the cytoplasmic tail for signal transduction and induces increased ICAM-1 surface expression; CD18 mAb blocks aggregation. B cell aggregation assay; CD40 mAb cross-linking; cytoplasmic tail deletion mutant of CD40; mAb blocking; energy/cation dependence assay; protein synthesis inhibitor Journal of immunology High 1706378
2022 CD11a (ITGAL) expression on microglia is critical for CX3CL1 receptor (Cx3cr1) expression and CX3CL1-directed motility, as well as CCL5 (glioma mitogen) production; CD11a-deficient microglia show impaired CX3CL1-directed migration and antibody-mediated CD11a inhibition reduces murine low-grade glioma growth in vivo. CD11a-knockout mice; in vitro CX3CL1 migration assay; CCL5 production assay; anti-CD11a neutralizing antibody treatment in vivo; RNA-seq Neuro-oncology Medium 34043012

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1988 ICAM, an adhesion ligand of LFA-1, is homologous to the neural cell adhesion molecule NCAM. Nature 642 3340213
1992 Divalent cation regulation of the function of the leukocyte integrin LFA-1. The Journal of cell biology 444 1346139
1998 Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis. Science (New York, N.Y.) 369 9685265
2008 Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 339 19064723
1997 Distinct roles for LFA-1 and CD28 during activation of naive T cells: adhesion versus costimulation. Immunity 316 9354475
2004 LFA-1 contributes an early signal for NK cell cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) 240 15356110
1997 LFA-1 is sufficient in mediating neutrophil emigration in Mac-1-deficient mice. The Journal of clinical investigation 236 9077544
1995 Ins and outs of LFA-1. Immunology today 232 7576051
2002 Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis and rheumatism 220 12115234
1991 CD40 signaling activates CD11a/CD18 (LFA-1)-mediated adhesion in B cells. Journal of immunology (Baltimore, Md. : 1950) 218 1706378
2007 CD8+ dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. Journal of immunology (Baltimore, Md. : 1950) 216 17641014
2018 LFA-1 in T Cell Migration and Differentiation. Frontiers in immunology 204 29774029
1999 Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. Journal of molecular biology 200 10493852
1991 Activation of LFA-1 through a Ca2(+)-dependent epitope stimulates lymphocyte adhesion. The Journal of cell biology 200 1703161
2022 Magnesium sensing via LFA-1 regulates CD8+ T cell effector function. Cell 189 35051368
2017 Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor. Molecular cell 186 29100055
2000 Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity. Nature 175 10766246
2009 RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice. Molecular therapy : the journal of the American Society of Gene Therapy 164 19997090
2005 A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes. The Journal of cell biology 163 15983060
2011 PLZF induces an intravascular surveillance program mediated by long-lived LFA-1-ICAM-1 interactions. The Journal of experimental medicine 159 21624939
1987 Absence of cell surface LFA-1 as a mechanism of escape from immunosurveillance. Lancet (London, England) 157 2887833
2015 F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse. The Journal of cell biology 140 25666810
2010 Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells. Journal of autoimmunity 133 20223637
1993 A novel LFA-1 activation epitope maps to the I domain. The Journal of cell biology 128 7680657
2007 The role of the integrin LFA-1 in T-lymphocyte migration. Immunological reviews 124 17624950
1999 The actin cytoskeleton regulates LFA-1 ligand binding through avidity rather than affinity changes. The Journal of biological chemistry 118 10480895
2017 Role of LFA-1 and ICAM-1 in Cancer. Cancers 113 29099772
1991 The role of LFA-1/ICAM-1 interactions during murine T lymphocyte development. Journal of immunology (Baltimore, Md. : 1950) 112 1680920
2012 Neutrophil arrest by LFA-1 activation. Frontiers in immunology 110 22701459
1994 Role of CD11a and CD11b in ischemic acute renal failure in rats. The American journal of physiology 106 7810691
2005 Importance of integrin LFA-1 deactivation for the generation of immune responses. The Journal of experimental medicine 95 15955836
1998 Transendothelial migration and trafficking of leukocytes in LFA-1-deficient mice. European journal of immunology 95 9645378
2006 Organization of the integrin LFA-1 in nanoclusters regulates its activity. Molecular biology of the cell 94 16855029
2006 Talin1 regulates TCR-mediated LFA-1 function. Journal of immunology (Baltimore, Md. : 1950) 88 17114441
2002 Age-dependent DNA methylation changes in the ITGAL (CD11a) promoter. Mechanisms of ageing and development 88 12020947
2017 Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration. Nature communications 83 29229906
2004 RanBPM is a phosphoprotein that associates with the plasma membrane and interacts with the integrin LFA-1. The Journal of biological chemistry 83 14722085
2017 Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program. Journal of immunology (Baltimore, Md. : 1950) 82 28784685
2003 Membrane cholesterol regulates LFA-1 function and lipid raft heterogeneity. Blood 80 12637320
1989 Suppression of human lymphocyte chemotaxis and transendothelial migration by anti-LFA-1 antibody. Journal of immunology (Baltimore, Md. : 1950) 80 2681413
2015 Micropatterning of TCR and LFA-1 ligands reveals complementary effects on cytoskeleton mechanics in T cells. Integrative biology : quantitative biosciences from nano to macro 77 26156536
1985 Immunologic studies with LFA-1- and Mo1-deficient lymphocytes from a patient with recurrent bacterial infections. Journal of immunology (Baltimore, Md. : 1950) 70 3156928
1991 Late treatment with anti-LFA-1 (CD11a) antibody prevents cerebral malaria in a mouse model. European journal of immunology 68 1679716
2010 RFX1 regulates CD70 and CD11a expression in lupus T cells by recruiting the histone methyltransferase SUV39H1. Arthritis research & therapy 67 21192791
2021 LFA-1 in T cell priming, differentiation, and effector functions. Trends in immunology 66 34266767
2005 Manifestations of inflammatory arthritis are critically dependent on LFA-1. Journal of immunology (Baltimore, Md. : 1950) 66 15749905
2014 Hypomethylation and overexpression of ITGAL (CD11a) in CD4(+) T cells in systemic sclerosis. Clinical epigenetics 64 25414732
2006 Induction of LFA-1-dependent neutrophil rolling on ICAM-1 by engagement of E-selectin. Microcirculation (New York, N.Y. : 1994) 63 16459323
2005 Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium. Blood 62 16269618
2010 Sustained LFA-1 cluster formation in the immune synapse requires the combined activities of L-plastin and calmodulin. European journal of immunology 61 20683899
2005 Spermine, a natural polyamine, suppresses LFA-1 expression on human lymphocyte. Journal of immunology (Baltimore, Md. : 1950) 61 15972654
1994 The ICAM-1/LFA-1 interaction in glomerular leukocytic accumulation in anti-GBM glomerulonephritis. Kidney international 61 7910869
1989 Expression of LFA-1 in non-Hodgkin's lymphoma. Cancer 61 2642732
2011 Migrational guidance of neutrophils is mechanotransduced via high-affinity LFA-1 and calcium flux. Journal of immunology (Baltimore, Md. : 1950) 60 21632714
2004 RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes. Nature immunology 60 15300248
2013 Essential role of CD11a in CD8+ T-cell accumulation and activation in adipose tissue. Arteriosclerosis, thrombosis, and vascular biology 58 24158516
1992 Regulation of LFA-1 avidity in human B cells. Requirements for dephosphorylation events for high avidity ICAM-1 binding. Journal of immunology (Baltimore, Md. : 1950) 57 1356124
2004 How T cells use LFA-1 to attach and migrate. Immunology letters 56 15081527
2001 CD98 induces LFA-1-mediated cell adhesion in lymphoid cells via activation of Rap1. FEBS letters 56 11165259
1995 Adhesive glycoproteins CD11a and CD18 are upregulated in the leukocytes from patients with ischemic stroke and transient ischemic attacks. Journal of the neurological sciences 55 7722533
1993 Generation and characterization of monoclonal antibodies against rabbit CD4, CD5 and CD11a antigens. Journal of immunological methods 55 7678632
2002 Effect of DNA methylation and chromatin structure on ITGAL expression. Blood 54 12036881
1985 Deficiency of two human leukocyte surface membrane glycoproteins (Mo1 and LFA-1). Federation proceedings 52 3891419
1985 Leukocyte LFA-1, OKM1, p150,95 deficiency syndrome: functional and biosynthetic studies of three kindreds. Federation proceedings 50 3891420
2006 The LFA-1 adhesion molecule is required for protective immunity during pulmonary Mycobacterium tuberculosis infection. Journal of immunology (Baltimore, Md. : 1950) 48 16585587
1995 Intratracheal injection of endotoxin and cytokines. IX. Contribution of CD11a/ICAM-1 to neutrophil emigration. The American journal of physiology 46 7491985
2010 Calpain 2 controls turnover of LFA-1 adhesions on migrating T lymphocytes. PloS one 45 21152086
1999 How LFA-1 binds to different ligands. Immunology today 45 10322304
2007 Aggregatibacter actinomycetemcomitans leukotoxin requires beta-sheets 1 and 2 of the human CD11a beta-propeller for cytotoxicity. Cellular microbiology 44 17587330
1996 Hyperoxia induces platelet activation and lung sequestration: an event dependent on tumor necrosis factor-alpha and CD11a. American journal of respiratory cell and molecular biology 41 8679214
2003 RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements. Blood 40 12855590
2013 A role for LFA-1 in delaying T-lymphocyte egress from lymph nodes. The EMBO journal 39 23443048
2018 The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse. Cell reports 38 29386139
2020 LFA-1 signals to promote actin polymerization and upstream migration in T cells. Journal of cell science 36 32907931
2013 Novel role of ICAM3 and LFA-1 in the clearance of apoptotic neutrophils by human macrophages. Apoptosis : an international journal on programmed cell death 36 23775590
2009 Statins inhibit NK-cell cytotoxicity by interfering with LFA-1-mediated conjugate formation. European journal of immunology 36 19424968
2012 A role for Rap2 in recycling the extended conformation of LFA-1 during T cell migration. Biology open 34 23213397
1993 Role of LFA-1/ICAM-1 in interleukin-2-stimulated lymphocyte proliferation. European journal of immunology 33 7903074
1986 Expression of the leukocyte functional molecule (LFA-1) on mouse platelets. Blood 33 3518835
2015 Different states of integrin LFA-1 aggregation are controlled through its association with tetraspanin CD9. Biochimica et biophysica acta 32 26003300
2010 An LFA-1 (alphaLbeta2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis. Journal of immunology (Baltimore, Md. : 1950) 31 20190141
2002 Lck tyrosine kinase is important for activation of the CD11a/CD18-integrins in human T lymphocytes. European journal of immunology 31 12115650
1998 A role for p21ras/MAP kinase in TCR-mediated activation of LFA-1. Journal of immunology (Baltimore, Md. : 1950) 31 9834054
2001 Molecular mechanisms of IL-2 gene regulation following costimulation through LFA-1. Journal of immunology (Baltimore, Md. : 1950) 30 11673532
2005 Tissue distribution and receptor-mediated clearance of anti-CD11a antibody in mice. Drug metabolism and disposition: the biological fate of chemicals 29 15673599
1990 The PMA-induced specific association of LFA-1 and talin in intact cloned T helper cells. The Journal of molecular and cellular immunology : JMCI 29 2150484
2004 Structure of an allosteric inhibitor of LFA-1 bound to the I-domain studied by crystallography, NMR, and calorimetry. Biochemistry 28 14992576
2022 RNA sequence analysis reveals ITGAL/CD11A as a stromal regulator of murine low-grade glioma growth. Neuro-oncology 27 34043012
2016 Attrition of memory CD8 T cells during sepsis requires LFA-1. Journal of leukocyte biology 27 27286793
2008 Effector and suppressor roles for LFA-1 during the development of experimental autoimmune encephalomyelitis. Journal of neuroimmunology 27 19010554
1998 Making a little affinity go a long way: a topological view of LFA-1 regulation. Cell adhesion and communication 27 9823476
1990 Two-way signalling through the LFA-1 lymphocyte adhesion receptor. BioEssays : news and reviews in molecular, cellular and developmental biology 27 2256906
2019 Transcriptome profiling of brain myeloid cells revealed activation of Itgal, Trem1, and Spp1 in western diet-induced obesity. Journal of neuroinflammation 26 31426806
2014 Adaptor regulation of LFA-1 signaling in T lymphocyte migration: Potential druggable targets for immunotherapies? European journal of immunology 25 25251823
1999 Critical role of CD11a (LFA-1) in therapeutic efficacy of systemically transferred antitumor effector T cells. Cellular immunology 25 10087180
2019 LFA-1 Controls Th1 and Th17 Motility Behavior in the Inflamed Central Nervous System. Frontiers in immunology 24 31681316
2013 Natural genetic variation of integrin alpha L (Itgal) modulates ischemic brain injury in stroke. PLoS genetics 24 24130503
2008 LFA-1 decreases the antigen dose for T cell activation in vivo. International immunology 24 18644832
2011 Central role of paxillin phosphorylation in regulation of LFA-1 integrins activity and lymphocyte migration. Cell adhesion & migration 23 22274710
1991 Regulation of LFA-1-mediated T cell adhesion by CD4. European journal of immunology 23 1826886