Affinage

CD2

T-cell surface antigen CD2 · UniProt P06729

Length
351 aa
Mass
39.4 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD2 is a T and NK cell surface immunoglobulin-superfamily glycoprotein that functions both as an adhesion molecule and as a costimulatory amplifier of antigen-receptor signaling (PMID:2951597, PMID:3102975, PMID:2566919, PMID:10562314). Its membrane-distal extracellular domain binds the GPI-anchored counter-receptor LFA-3/CD58 in humans and CD48 in mice through a hypervariable-like region of its first Ig domain, an interaction that requires N-glycosylation at Asn65 to maintain the binding-competent fold (PMID:2951597, PMID:3102975, PMID:3313052, PMID:2444890, PMID:1383383, PMID:1385399). This adhesion is constitutively active at rest and complements the inducible LFA-1 system; TCR engagement subsequently increases CD2 surface number, 2D affinity, and immobilization at the contact zone to strengthen conjugate formation, a regulated avidity that depends on the COOH-terminal asparagine of the cytoplasmic tail and is mechanistically separable from CD2's signaling output (PMID:2566919, PMID:1672642, PMID:1353888, PMID:7901319, PMID:17168569). The cytoplasmic domain couples ligand engagement to the TCR signalosome: CD2 associates with CD3ζ/ε and the Src-family kinases p56lck and p59fyn, and CD3ζ is the essential downstream subunit transducing CD2 signals in both T and NK cells, with p59fyn acting as the critical upstream kinase phosphorylating PLCγ1, Vav, and other substrates (PMID:1351920, PMID:1346934, PMID:8093441, PMID:11093170). Through this complex CD2 synergizes with the TCR to drive PLCγ1 activation, calcium flux, and IL-2 production, and recent work places CD2-CD48 cis interactions on the same T cell membrane—rather than trans engagement of APC ligand—as the requirement for activation (PMID:17220479, PMID:19494291, PMID:35930657). The tail also engages dedicated adaptors: CD2BP2 binds PPPGHR motifs via a GYF module to enhance CD2-specific IL-2 output, while CD2BP1/PSTPIP1 binds via its SH3 domain and downregulates adhesion by coupling PTP-PEST to clustered CD2 (PMID:9843987, PMID:9857189). Spatially, CD2 concentrates at the immunological synapse, forming an outer 'CD2 corolla' that captures costimulatory receptors and amplifies proximal SFK/LAT/PLCγ signaling, and CD2 costimulation drives AMPK-dependent polarization of lytic granules toward the MTOC in cytotoxic T cells (PMID:32929275, PMID:32398348). (Findings concerning CD2AP—actin binding, nephrin/polycystin linkage, and cytokinesis (PMID:12217865, PMID:15800069)—describe a distinct protein and are not part of CD2 receptor biology.)

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1987 High

    Establishing that CD2 is a high-affinity adhesion receptor for LFA-3/CD58 defined its founding molecular function and placed both partners in the Ig superfamily.

    Evidence Purified-protein binding and rosetting inhibition assays; cDNA cloning and sequence analysis of LFA-3

    PMID:2951597 PMID:3102975 PMID:3313052

    Open questions at the time
    • Did not localize the binding interface on CD2
    • Did not establish whether adhesion contributes to signaling
  2. 1987 High

    Mapping the LFA-3 site to the first Ig domain and showing natural ligand delivers an activation signal connected adhesion structure to function and to the 'alternative pathway' of T cell activation.

    Evidence Systematic CD2 mutagenesis with binding readouts; T cell stimulation with natural ligand and activating antibodies

    PMID:2444890 PMID:3102975

    Open questions at the time
    • Did not define the cytoplasmic signaling machinery
    • Did not separate adhesion from signal transduction
  3. 1988 High

    Demonstrating that CD2 activation requires an intact CD3-Ti complex established interdependence between the CD2 and TCR pathways rather than fully independent signaling.

    Evidence CD3-Ti-negative Jurkat mutants with phosphoinositide/Ca2+/IL-2 readouts and TCR reconstitution rescue

    PMID:2901344

    Open questions at the time
    • Did not identify which TCR subunit is the coupling element
    • Did not address adhesion-only contributions
  4. 1989 High

    Showing that cytoplasmic-tailless CD2 still enhances antigen-specific responses dissected adhesion per se from signal transduction as separable contributors to activation.

    Evidence CD2 cytoplasmic truncation mutants in antigen-specific hybridomas with LFA-3+ APCs

    PMID:2566919

    Open questions at the time
    • Did not define the signaling motifs in the retained vs. deleted tail
  5. 1991 High

    Biophysical reconstitution showed ligand lateral mobility strengthens CD2 adhesion and that CD2 adhesion is constitutively active, distinguishing it from inducible LFA-1.

    Evidence Planar bilayers with GPI vs. transmembrane LFA-3, FRAP, flow adhesion assays; pharmacological modulation of adhesion

    PMID:1672642 PMID:1717480

    Open questions at the time
    • Did not connect adhesion strength to downstream signaling magnitude in primary cells
  6. 1992 High

    Chimeric-receptor reconstitution identified CD3ζ as the necessary and sufficient subunit coupling CD2 to signaling in both T and NK cells, resolving the coupling element left open in 1988.

    Evidence CD8α/CD3ζ and CD16 chimeras in TCR-negative Jurkat with Ca2+, PTK, and IL-2 readouts; wild-type vs. truncated CD3ζ

    PMID:1346934 PMID:1351920

    Open questions at the time
    • Did not define the physical linkage between CD2 tail and CD3ζ
    • Did not enumerate the kinases recruited
  7. 1992 High

    Identifying CD48 as the mouse counter-receptor and Asn65/N-glycan as essential for ligand binding completed the ligand map and defined a glycan-dependent adhesion fold.

    Evidence CD2-Ig fusion screening with microsequencing and blocking; deglycosylation and Asn65→Gln mutagenesis with binding/MS

    PMID:1383383 PMID:1385399

    Open questions at the time
    • Did not address cis vs. trans engagement of CD48
  8. 1992 High

    Defining TCR-induced avidity regulation and pinning it to the COOH-terminal asparagine revealed a dynamic adhesion-tuning function distinct from CD2 signaling output.

    Evidence CD2 cytoplasmic point/deletion mutants in T cell lines with CD58-avidity and antigen-proliferation assays

    PMID:1353888 PMID:7901319

    Open questions at the time
    • Did not identify the trans-acting regulator binding the C-terminal asparagine region
  9. 1993 Medium

    Co-IP/kinase work assembled the CD2 signaling complex (p56lck, p59fyn, CD3ζ/ε) and linked avidity upregulation to PTK/PKC/cAMP inputs converging on the C-terminal asparagine.

    Evidence In vitro kinase assays on CD2 immunoprecipitates, immunofluorescence capping; pharmacological PTK/PKC/cAMP dissection with mutants

    PMID:7681075 PMID:7912674 PMID:8093441

    Open questions at the time
    • Co-IP associations not reconstituted to establish directness
    • Single-lab kinase assays
  10. 1998 High

    Cloning CD2BP2 and CD2BP1/PSTPIP1 identified dedicated tail adaptors with opposing effects on CD2 signaling vs. adhesion, defining a proline-motif-based regulatory module.

    Evidence Interaction trap cloning, NMR of CD2BP2 GYF domain, SH3 binding assays, co-localization, IL-2 and adhesion readouts

    PMID:9843987 PMID:9857189

    Open questions at the time
    • Did not establish how adaptor engagement is temporally regulated during synapse formation
  11. 1998 Medium

    Demonstrating a p56lck-independent JNK/AP-1 arm of CD2 signaling showed mechanistic divergence between CD2 and TCR signaling beyond shared components.

    Evidence CD2 stimulation in p56lck-deficient lines with JNK assay, AP-1 binding, and IL-2 promoter reporter

    PMID:9727049

    Open questions at the time
    • Did not identify the kinase relay upstream of JNK in the absence of Lck
    • Single-lab study
  12. 1999 Medium

    Identifying CD2-induced CD5 dephosphorylation and SHP-1 activation, and later p62dok recruitment, exposed negative-regulatory nodes specific to CD2 signaling.

    Evidence Reciprocal co-IP in CD3/CD2-deficient Jurkat with SHP-1 activity; p62dok overexpression with Ca2+/PLCγ1/ERK readouts

    PMID:10510361 PMID:11254695

    Open questions at the time
    • Did not establish physiological roles in primary T cells
    • Single-lab gain/loss studies
  13. 2000 High

    Genetic knockout and transgenic models established p59fyn as the critical CD2 kinase and quantified CD2's additive contribution with LFA-1 to lowering the antigen activation threshold.

    Evidence Human CD2-transgenic fyn-/- mice and CD2-deficient TCR-transgenic mice with Ca2+, MAPK, conjugate, and in vivo LCMV readouts

    PMID:10562314 PMID:11093170

    Open questions at the time
    • Did not resolve spatial organization of CD2 signaling at the synapse
  14. 2003 High

    Showing that nanoscale intermembrane spacing controls CD2 adhesion and synapse organization linked CD2 dimensions directly to TCR triggering geometry.

    Evidence Extended CD48 chimeras with electron tomography, confocal synapse imaging, and bilayer adhesion assays

    PMID:18826951

    Open questions at the time
    • Did not map the molecular sensors that read intermembrane distance
  15. 2006 Medium

    Live imaging revealed CD2 concentration in an early central invagination and quantified the activation-induced increases in CD2 number, 2D affinity, and immobilization underlying avidity enhancement.

    Evidence Live microscopy of T cell-APC conjugates; quantitative imaging, 2D affinity measurement, and FRAP

    PMID:16982875 PMID:17168569

    Open questions at the time
    • Single-lab imaging studies
    • Did not directly link invagination dynamics to defined signaling molecules
  16. 2009 Medium

    Single-molecule and reconstitution studies placed CD2 as an actin-dependent organizer that coalesces TCRζ/Lck/LAT microdomains and relays CD2→CD48→LAT to the TCR signalosome.

    Evidence Jurkat on CD58-only bilayers with single-molecule TIRF tracking; co-IP epistasis of CD2/CD48/LAT/Lck with IL-2 assays

    PMID:19398758 PMID:19494291

    Open questions at the time
    • Co-IP epistasis not reconstituted with purified components
    • Did not resolve cis vs. trans CD48 source
  17. 2012 Medium

    CD2-CD48/CD58 interaction was shown to be required for NK cell membrane nanotube formation and cytotoxic function, extending CD2's role to NK effector architecture.

    Evidence Stable CD2 expression in CD2-negative YTS cells, blocking antibodies, live imaging, cytotoxicity assays

    PMID:23112830

    Open questions at the time
    • Single-lab study
    • Did not define the signaling pathway driving nanotube formation
  18. 2020 High

    Super-resolution imaging and phosphoproteomics defined the outer 'CD2 corolla' that captures costimulatory receptors to amplify proximal signaling and a CD2-driven AMPK axis polarizing lytic granules toward the MTOC.

    Evidence Super-resolution/confocal IS imaging with copy-number and tail-truncation manipulation; phosphoproteomics with AMPK and granule-polarization functional validation in primary human T cells

    PMID:32398348 PMID:32929275

    Open questions at the time
    • Did not fully define the tail motifs controlling corolla formation at residue level
    • Mechanism of AMPK enrichment on granule-adjacent lysosomes not resolved
  19. 2022 High

    New knockouts, FRET, and CD2 interactome mass spectrometry redefined the activation requirement as CD2-CD48 cis interactions on the T cell, with CD2 physically associating with the TCR complex and Lck.

    Evidence CD2 and CD48 knockout mouse strains, FRET in non-immune cells, mass spectrometry of CD2 knock-in T cells, TCR phosphorylation and cytotoxicity assays

    PMID:35930657

    Open questions at the time
    • Did not structurally resolve the cis CD2-CD48 complex
    • Did not reconcile cis requirement with prior trans-adhesion models mechanistically

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CD2 cytoplasmic-tail motifs, cis CD48 engagement, and corolla positioning are integrated into a single physical mechanism that couples adhesion geometry to TCR-proximal signaling amplification remains unresolved.
  • No high-resolution structure of the assembled CD2 signaling complex with CD3ζ/Lck
  • Quantitative rules linking corolla composition to signal amplification undefined
  • Reconciliation of cis vs. trans CD2-CD48 engagement in vivo incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098631 cell adhesion mediator activity 5 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 6
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4 R-HSA-1500931 Cell-Cell communication 3
Partners
CD2BP2CD3ZCD48CD5CD58FYNLCKPSTPIP1
Complex memberships
CD2 corollaTCR/CD3-CD2 signaling complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 CD2 (T lymphocyte glycoprotein) binds the cell surface ligand LFA-3 (CD58) with high affinity, mediating adhesion of lymphoid cells. Purified CD2 inhibition of rosetting; cell adhesion assays with purified LFA-3 Nature High 2951597 3102975
1987 LFA-3 (the ligand for CD2) is a phospholipid-linked (GPI-anchored) membrane protein whose extracellular domain shares significant homology with CD2, placing both in the immunoglobulin superfamily. cDNA cloning and transient expression in mouse cells; sequence analysis Nature High 3313052
1987 Binding of the natural CD2 ligand (T11TS/LFA-3) to CD2 on resting T cells induces reactivity to mitogenic anti-CD2 antibody stimuli, establishing CD2-ligand interaction as providing one signal required for alternative-pathway T cell activation. T cell stimulation assays with natural cell-surface ligand and monoclonal antibodies Nature High 3102975
1987 Mutational analysis mapped the LFA-3 binding site of CD2 to the first extracellular domain, corresponding to immunoglobulin variable region hypervariable sequences; activating anti-CD2 antibodies bind overlapping epitopes in regions 1 and 3, supporting the model that they mimic LFA-3 binding. Systematic mutagenesis of CD2 followed by antibody binding and LFA-3 binding assays Nature High 2444890
1988 CD2-mediated T cell activation requires phosphoinositide turnover that is linked to the CD3-Ti complex; CD3-Ti-negative Jurkat mutants cannot be activated through either CD3 or CD2 pathways, and this is rescued by TCR reconstitution, demonstrating interdependence of the two pathways. Jurkat mutant cell lines (CD3-Ti-negative); phosphoinositide turnover assays; Ca2+ mobilization; IL-2 gene induction; DNA transfection rescue The EMBO journal High 2901344
1989 The CD2 extracellular adhesion domain (LFA-3 binding) is functionally separable from its cytoplasmic signal transduction domain; CD2 mutants lacking functional cytoplasmic domain still enhance antigen-specific T cell responses by up to 400% when LFA-3 is present on the same APC, demonstrating that adhesion per se contributes to T cell activation. Transfection of CD2 cytoplasmic-domain truncation mutants into antigen-specific T cell hybridoma; antigen-specific proliferation assays with LFA-3-expressing APCs Nature High 2566919
1990 CD2 is physically associated with CD45 (a tyrosine phosphatase) on the surface of human T lymphocytes, providing a molecular basis for the co-mitogenic effect of anti-CD45 and anti-CD2 antibodies. Chemical crosslinking followed by co-immunoprecipitation Nature Medium 1970422
1991 Lateral mobility of GPI-anchored LFA-3 on supported lipid bilayers enhances CD2-mediated T cell adhesion strength by facilitating receptor accumulation and bond formation in the contact zone; mobile GPI-LFA-3 strengthens adhesion faster than immobile transmembrane-LFA-3 at low ligand densities. Reconstituted planar lipid bilayers with two LFA-3 isoforms; static and laminar-flow cell adhesion assays; fluorescence recovery after photobleaching (FRAP) The Journal of cell biology High 1717480
1991 CD2 adhesion function is constitutively active in non-activated T cells and is not detectably modulated by TCR stimulation, protein kinase C activation, or cAMP; in contrast, LFA-1 adhesion is minimal at rest and upregulated by TCR signaling, demonstrating complementary roles of CD2 and LFA-1 in initiating vs. sustaining cell-cell contact. Cell adhesion assays; pharmacological modulation (PKC activators, cAMP); flow cytometry European journal of immunology Medium 1672642
1992 CD2-mediated signal transduction in T lymphocytes requires the CD3 zeta cytoplasmic domain; expression of a CD8α/CD3ζ chimeric receptor in TCR-negative Jurkat cells restored Ca2+ mobilization, protein tyrosine kinase activation, and IL-2 secretion upon CD2 stimulation, demonstrating that CD3ζ is a necessary and sufficient TCR subunit for coupling CD2 to signaling. CD8α/CD3ζ chimeric receptor transfection into TCR-negative Jurkat; Ca2+ mobilization; protein tyrosine kinase assay; IL-2 secretion The Journal of experimental medicine High 1351920
1992 On NK cells, CD16 (FcγRIII) is functionally equivalent to the TCR for coupling CD2 to signaling; transfecting a transmembrane CD16 into TCR-negative Jurkat cells (which express endogenous CD3ζ) restores CD2 signaling; CD2 signaling further requires a wild-type CD3ζ subunit, establishing CD3ζ as the essential downstream effector of CD2-triggered signaling in both T and NK cells. CD16 cDNA transfection into TCR-negative Jurkat; wild-type vs. truncated CD3ζ T-T hybridomas; Ca2+ mobilization; IL-2 production Proceedings of the National Academy of Sciences of the United States of America High 1346934
1992 CD48 is the counter-receptor for mouse CD2; identified by generating a CD2-Ig fusion protein to screen for binding partners on T cell lines; confirmed by protein microsequencing, anti-CD48 antibody blocking, and soluble CD48 inhibition; anti-CD48 antibody inhibited PHA responses and augmented anti-CD3 responses of splenic T cells. Chimeric mCD2-IgG1 fusion protein; mAb screening; protein microsequencing; soluble recombinant CD48 blocking assay; T cell proliferation assays The Journal of experimental medicine High 1383383
1992 TCR-CD3 signaling rapidly increases CD2 avidity for CD58 (LFA-3); the carboxyl-terminal asparagine of the CD2 cytoplasmic domain is essential for this avidity regulation but not for CD2-mediated signaling; cell lines incapable of CD2 avidity regulation show marked deficiency in antigen-specific T cell responses. CD2 cytoplasmic domain point mutants transfected into T cell lines; CD58-binding avidity assay; antigen-specific proliferation assays Proceedings of the National Academy of Sciences of the United States of America High 1353888
1992 N-glycosylation at Asn65 in the CD2 extracellular domain is essential for CD2-CD58 binding; deglycosylated CD2 or Asn65→Gln65 mutant CD2 fails to bind CD58 or conformational anti-CD2 antibodies, indicating N-glycans stabilize the adhesion domain structure. Enzymatic deglycosylation; site-directed mutagenesis (Asn65→Gln); CD58-binding assays; electrospray ionization mass spectrometry characterization of glycoforms The Journal of biological chemistry High 1385399
1993 The CD2 cytoplasmic domain contains two structurally and functionally separable regions: one required for signal transduction (IL-2 production) and a distinct COOH-terminal 21-aa region required for TCR-induced avidity regulation for CD58; regulated avidity and signaling each independently contribute to optimal antigen-specific T cell responses. Series of CD2 cytoplasmic domain deletion/point mutants stably transfected in antigen-specific T cell hybridoma; IL-2 production assays; CD58-avidity assays The Journal of experimental medicine High 7901319
1993 TCR-initiated upregulation of CD2 avidity for CD58 requires both protein tyrosine kinases and protein kinase C activity; cAMP also upregulates CD2 avidity independently of PKC and PTK; all three stimuli require the COOH-terminal asparagine of CD2 cytoplasmic domain as a common structural element, distinguishing this regulatory mechanism from LFA-1 and CD8 avidity regulation. Pharmacological inhibitors of PTK and PKC; cAMP elevation; CD2 point mutants; rosetting and CD58-binding avidity assays in transfected T cell hybridomas Journal of immunology Medium 7681075
1993 CD2 associates with protein tyrosine kinases p56lck and p59fyn, and with CD3 zeta and epsilon chains, forming a multimolecular signaling complex in T lymphocytes; induction of T cell unresponsiveness (by CD3/TCR modulation) uncouples zeta and epsilon from CD2 while p56lck and p59fyn associations remain, correlating with loss of CD2-mediated proliferation. In vitro kinase assays on CD2 immunoprecipitates from Brij-58 T lymphocyte lysates; double indirect immunofluorescence with capping European journal of immunology Medium 8093441
1994 CD2 forms a signaling complex with CD3 zeta chain and the Src-family kinase p59fyn in T lymphocytes, identified by in vitro kinase assays on CD2 immunoprecipitates and confirmed by double indirect immunofluorescence capping in viable T lymphocytes. In vitro kinase assays; immunoprecipitation; double indirect immunofluorescence capping European journal of immunology Medium 7912674
1998 A cytoplasmic protein CD2BP2 binds directly to two PPPGHR motifs in the CD2 cytoplasmic domain via a novel 17-aa GYF-containing proline-binding module distinct from SH3 and WW domains; over-expression of the CD2BP2 binding domain in Jurkat cells enhances IL-2 production upon CD2 crosslinking but not TCR crosslinking. Interaction trap cloning; mutagenesis; NMR structure of CD2BP2 binding domain; functional over-expression in Jurkat cells with IL-2 production assay Proceedings of the National Academy of Sciences of the United States of America High 9843987
1998 CD2BP1 (a cdc15-like adaptor protein, also called PSTPIP1) binds directly to the CD2 cytoplasmic sequence KGPPLPRPRV via its SH3 domain; upon ligand-induced CD2 clustering, CD2BP1 redistributes from cytosol to the membrane co-localizing with CD2 and downregulates CD2-stimulated adhesion, apparently by coupling PTP-PEST to CD2. Interaction trap cloning; direct SH3 domain binding assay; immunofluorescence co-localization; CD2 adhesion assays with CD2BP1 expression The EMBO journal High 9857189
1998 CD2 contains a p56lck-independent signaling pathway; CD2-mediated IL-2 production occurs via activation of Jun kinase (JNK) in cell lines lacking p56lck, with c-Jun/c-Fos binding to the AP-1 site driving IL-2 promoter activity, demonstrating mechanistic divergence between CD2 and TCR signaling. p56lck-deficient T cell lines; CD2 stimulation; JNK kinase assay; AP-1 transcription factor binding; IL-2 promoter activity The Journal of biological chemistry Medium 9727049
1999 CD2 physically associates with CD5 in T lymphocytes independently of CD3; CD2 cross-linking leads to dephosphorylation of CD5 (in contrast to CD3 stimulation which phosphorylates CD5) correlated with enhanced SHP-1 phosphatase activity, identifying CD5 phosphorylation state as a CD2-regulated signaling node. Co-immunoprecipitation in CD3-deficient and CD2-deficient Jurkat cells; phosphotyrosine western blotting; SHP-1 phosphatase activity assay Journal of immunology Medium 10510361
2000 p59fyn is a critical upstream kinase in the CD2 signaling pathway; in fyn-/- mice expressing transgenic human CD2, CD2-induced Ca2+ mobilization, MAPK activation, and T cell proliferation are markedly reduced, while TCR-triggered proliferation is unaffected; CD2 pathway substrates of fyn include PLCγ1, Vav, PKCθ, Dok, FAK, and Pyk2. Human CD2 transgenic fyn-/- mice; T cell stimulation assays; Ca2+ flux; MAPK assays; substrate phosphorylation analysis; proliferation assays European journal of immunology High 11093170
2000 CD2 and LFA-1 facilitate T cell activation additively; absence of both CD2-CD48 and LFA-1-ICAM-1 interactions in CD2-deficient mice shifts the antigen dose-response by ~100-fold; CD2 absence affects conjugate formation, TCR triggering, and Ca2+ flux at low antigen density. CD2-deficient mice crossed with TCR-transgenic mice; T cell-APC conjugate formation assay; TCR triggering assay; Ca2+ flux measurement; in vivo LCMV infection The Journal of experimental medicine High 10562314
2001 p62dok is a negative regulator of CD2 signaling; over-expression of p62dok in Jurkat cells inhibits CD2-mediated (but not CD3-mediated) Ca2+ increase, PLCγ1 activation, and ERK1/2 activation; CD2 (but not CD3) stimulation induces p62dok and RasGAP recruitment to the plasma membrane. Stable over-expression of p62dok in Jurkat cells; Ca2+ flux; PLCγ1 activation assay; ERK1/2 phosphorylation; membrane fractionation; NF-AT reporter assay Journal of immunology Medium 11254695
2002 CD2AP directly binds filamentous actin (F-actin) through its COOH terminus, acting as a direct adapter between the actin cytoskeleton and membrane proteins such as nephrin and polycystin-2; disruption of the actin cytoskeleton disorganizes endogenous CD2AP distribution. F-actin coprecipitation assay with purified CD2AP fusion proteins; cytoskeletal fractionation by differential centrifugation; fluorescence co-localization in cultured cells; actin depolymerization experiments American journal of physiology. Renal physiology High 12217865
2002 Alefacept (LFA-3/IgG1 fusion protein) mediates apoptosis of CD2+ T cells by bridging CD2 on T cells with CD16 (FcγRIII) on NK cells; signaling is transduced through CD16, not CD2; confirmed using IgG1 CH2 domain Fc mutants that ablate FcγR binding, and in human CD2-transgenic mice. Alefacept Fc-region amino acid substitution mutants; ERK phosphorylation; CD25 expression; granzyme B release; human CD2-transgenic mouse model Journal of immunology High 11970990
2003 Nanoscale increases in intermembrane spacing (from 12.8 nm with CD48-WT to 14.7–15.6 nm with extended CD48 chimeras) reduce CD2-mediated adhesion efficiency 10-fold and reorganize the immunological synapse, sequestering TCR away from its ligand. CD48 chimeras with additional Ig domains; electron tomography of contact areas; confocal imaging of immunological synapses; quantitative adhesion assays with planar bilayers The Journal of biological chemistry High 18826951
2005 CD2AP is required for cytokinesis in HeLa cells; it localizes to the midbody during telophase (as a membrane-associated, not microtubule-associated, protein), interacts with the cleavage furrow protein anillin (by yeast two-hybrid), and siRNA-mediated knockdown of CD2AP causes cell multinucleation/failure of cell separation; CD2AP is phosphorylated during mitosis. Immunofluorescence localization; SH3 domain overexpression; siRNA knockdown; yeast two-hybrid; phosphorylation analysis Molecular biology of the cell High 15800069
2006 CD2 concentrates in a large T cell invagination at the center of the T cell-APC interface within 1 minute of contact formation; dissolution of this invagination and CD2 engagement are required for effective proximal TCR signaling; CD2 is the most prominently internalized receptor in this structure. Live fluorescence microscopy of T cell-APC conjugates; antibody blocking; quantitative receptor tracking Journal of immunology Medium 16982875
2006 T cell activation causes a 1.5-fold increase in cell-surface CD2 numbers, a 2.5-fold increase in 2D affinity for CD58, and immobilization of ligated CD2 at the contact zone (reduced lateral mobility); these combined changes substantially enhance CD2 avidity and strengthen T cell-APC adhesion. Quantitative fluorescence imaging of CD2 numbers; 2D affinity measurement; FRAP of CD2 on resting vs. activated T cells ACS chemical biology Medium 17168569
2007 CD2-CD58 interaction synergizes with TCR to activate PLC-γ1 at the immunological synapse; blocking CD2-CD58 interaction reduces PLCγ1 recruitment to the IS and impairs phosphorylation of PLCγ1 at regulatory Tyr783, demonstrating that CD2 costimulation enhances TCR-induced calcium signaling through PLCγ1. Anti-CD58 antibody blocking; single-cell Ca2+ imaging; PLCγ1 immunofluorescence at IS; phospho-PLCγ1 (Tyr783) western blot International immunology Medium 17220479
2009 CD2 ligation by CD58 (in the absence of TCR activation) induces signaling through actin-dependent coalescence of TCR-ζ, Lck, and LAT into plasma membrane microdomains; when TCR and CD2 are co-activated, they initially co-localize then spatially segregate into separate zones, potentially enabling synergistic signaling. Jurkat T cells on planar lipid bilayers (CD58 only, without TCR ligand); single-molecule tracking; live TIRF microscopy; co-localization analysis The Journal of cell biology High 19398758
2009 CD2 acts as a master adaptor linking Lck and CD48 to the TCR/CD3 complex during T cell activation; CD48 (GPI-anchored) is recruited to the immobilized TCR/CD3 complex in a CD2-dependent manner, and CD48 in turn recruits LAT to the TCR complex, establishing a hierarchical CD2→CD48→LAT signaling relay. Co-immunoprecipitation of TCR/CD3 complex with CD2, CD48, LAT, and Lck; T cell IL-2 production assays; knockdown experiments; CD2- and CD48-deficient cell analysis Journal of immunology Medium 19494291
2012 CD2-CD58/48 receptor-ligand interaction is required for membrane nanotube formation by human NK cells; stable CD2 expression in CD2-negative NK cell line YTS enables nanotube formation and improves cytotoxic function; CD2 localizes to nanotube tips; blocking CD2 receptor-ligand interactions prevents nanotube formation. Stable CD2 transfection into CD2-negative YTS NK cells; quantitative live-cell fluorescence microscopy; blocking antibodies; cytotoxicity assays PloS one Medium 23112830
2020 CD2 localizes to the outer edge of the mature immunological synapse (the 'CD2 corolla'), where it captures engaged co-stimulatory receptors (CD28, ICOS, CD226, SLAM-F1) and amplifies active phosphorylated SFK, LAT, and PLC-γ signaling by 77% compared to central CD2; corolla formation depends on CD2 copy number and specific cytoplasmic tail motifs; PD-1 invades the corolla and buffers CD2-mediated signaling amplification. Super-resolution imaging and confocal microscopy of IS with primary human T cells and artificial APCs; CD2 copy number manipulation; cytoplasmic tail truncation mutants; pSFK/LAT/PLCγ quantification; PD-1 co-engagement experiments Nature immunology High 32929275
2020 CD2 costimulation drives AMPK-dependent polarization of lytic granules toward the MTOC in CD8+ CTLs; phosphoproteomics revealed 616 CD2-regulated phosphorylation events including AMPK pathway activation; AMPK enriched on lysosomes adjacent to granules drives this polarization. Phosphoproteomics of CD2-stimulated primary human CD8+ T cells; AMPK activity assays; lytic granule polarization imaging; lysosome-granule proximity analysis; functional cytotoxicity assays Science signaling High 32398348
2022 CD2-CD48 cis interactions (within the same T cell membrane) are required for T cell activation; CD48 on APCs is dispensable for T cell activation (except during cytotoxicity), while T cell-intrinsic CD48 is necessary; FRET confirmed CD2-CD48 cis interactions in non-immune cells; mass spectrometry of CD2 knock-in T cells revealed that CD2 interacts with TCR complex components and Lck, correlating CD2 function with its association with the TCR signalosome. New CD2 and CD48 knockout mouse strains; FRET in non-immune cells; mass spectrometry of CD2 tag knock-in T cells; TCR signaling (protein tyrosine phosphorylation) assays; cytotoxicity assays Science immunology High 35930657

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1987 An LFA-3 cDNA encodes a phospholipid-linked membrane protein homologous to its receptor CD2. Nature 742 3313052
1987 The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3. Nature 520 2951597
1987 Alternative pathway activation of T cells by binding of CD2 to its cell-surface ligand. Nature 275 3102975
1992 CD48 is a counter-receptor for mouse CD2 and is involved in T cell activation. The Journal of experimental medicine 247 1383383
1989 CD2-mediated adhesion facilitates T lymphocyte antigen recognition function. Nature 241 2566919
1990 Association of CD2 and CD45 on human T lymphocytes. Nature 184 1970422
1991 Influence of receptor lateral mobility on adhesion strengthening between membranes containing LFA-3 and CD2. The Journal of cell biology 174 1717480
1987 Similarities in sequences and cellular expression between rat CD2 and CD4 antigens. The Journal of experimental medicine 169 3102667
1987 Monoclonal antibody and ligand binding sites of the T cell erythrocyte receptor (CD2). Nature 162 2444890
1989 The structural biology of CD2. Immunological reviews 161 2576417
2001 Activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family. Journal of immunology (Baltimore, Md. : 1950) 159 11698418
1988 Interdependence of CD3-Ti and CD2 activation pathways in human T lymphocytes. The EMBO journal 153 2901344
1988 The structure of the human CD2 gene and its expression in transgenic mice. The EMBO journal 149 2901953
1992 Development and function of T cells in mice with a disrupted CD2 gene. The EMBO journal 143 1358605
2002 CD2-associated protein directly interacts with the actin cytoskeleton. American journal of physiology. Renal physiology 129 12217865
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1998 CD2 and the nature of protein interactions mediating cell-cell recognition. Immunological reviews 121 9700513
2020 A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals. Nature immunology 107 32929275
1988 Unusual expression of CD2 in sheep: implications for T cell interactions. European journal of immunology 106 2462499
1991 Anti-CD2 antibodies induce T cell unresponsiveness in vivo. The Journal of experimental medicine 100 1682413
1999 CD2 sets quantitative thresholds in T cell activation. The Journal of experimental medicine 99 10562314
1992 CD3 zeta dependence of the CD2 pathway of activation in T lymphocytes and natural killer cells. Proceedings of the National Academy of Sciences of the United States of America 99 1346934
2002 Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells. Journal of immunology (Baltimore, Md. : 1950) 98 11970990
1992 Correlation of CD2 expression with PML gene breakpoints in patients with acute promyelocytic leukemia. Blood 97 1353379
1994 Anti-CD2 receptor and anti-CD2 ligand (CD48) antibodies synergize to prolong allograft survival. The Journal of experimental medicine 95 7903681
2009 The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells. The Journal of cell biology 90 19398758
1998 Identification of a proline-binding motif regulating CD2-triggered T lymphocyte activation. Proceedings of the National Academy of Sciences of the United States of America 88 9843987
1991 Complementary roles for CD2 and LFA-1 adhesion pathways during T cell activation. European journal of immunology 80 1672642
1998 A cdc15-like adaptor protein (CD2BP1) interacts with the CD2 cytoplasmic domain and regulates CD2-triggered adhesion. The EMBO journal 79 9857189
1995 CD2 regulates responsiveness of activated T cells to interleukin 12. The Journal of experimental medicine 78 7544396
1992 The CD3 zeta cytoplasmic domain mediates CD2-induced T cell activation. The Journal of experimental medicine 74 1351920
2005 Clues to CD2-associated protein involvement in cytokinesis. Molecular biology of the cell 64 15800069
2002 Studies on the interaction between Cd(2+) ions and DNA. Journal of inorganic biochemistry 64 12031800
2003 CD2-associated protein and glomerular disease. Lancet (London, England) 62 14643126
1991 Cadmium (Cd2+) disrupts Ca(2+)-dependent cell-cell junctions and alters the pattern of E-cadherin immunofluorescence in LLC-PK1 cells. Biochemical and biophysical research communications 61 1764062
2008 Nanoscale increases in CD2-CD48-mediated intermembrane spacing decrease adhesion and reorganize the immunological synapse. The Journal of biological chemistry 58 18826951
2000 Coordinate regulation of T cell activation by CD2 and CD28. Journal of immunology (Baltimore, Md. : 1950) 57 10725714
1999 Circulating CD2+ monocytes are dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 57 10570278
1992 A distinct cytoplasmic domain of CD2 regulates ligand avidity and T-cell responsiveness to antigen. Proceedings of the National Academy of Sciences of the United States of America 56 1353888
2001 Cloning, expression, and function of BLAME, a novel member of the CD2 family. Journal of immunology (Baltimore, Md. : 1950) 54 11313408
1988 Role of CD2 cross-linking in cytoplasmic calcium responses and T cell activation. European journal of immunology 54 2461308
1992 N-glycosylation is required for human CD2 immunoadhesion functions. The Journal of biological chemistry 53 1385399
1995 Mammalian CD2 is an effective heterologous marker of the cell surface in Drosophila. Developmental biology 52 7729601
1993 Conditional expression and oncogenicity of c-myc linked to a CD2 gene dominant control region. International journal of cancer 51 8473043
2005 CD2-associated protein (CD2AP) expression in podocytes rescues lethality of CD2AP deficiency. The Journal of biological chemistry 50 15951437
1991 CD2 can mediate TCR/CD3-independent T cell activation. Journal of immunology (Baltimore, Md. : 1950) 49 1674520
1988 Identification of a CD2- CD3+ T cell receptor-gamma+ peripheral blood lymphocyte subpopulation. Journal of immunology (Baltimore, Md. : 1950) 48 2895149
2022 Cis interactions between CD2 and its ligands on T cells are required for T cell activation. Science immunology 47 35930657
2003 Forced detachment of the CD2-CD58 complex. Biophysical journal 45 12668431
1989 Expression and function of CD2 during murine thymocyte ontogeny. European journal of immunology 44 2575032
1993 Signal transduction pathways involved in T cell receptor-induced regulation of CD2 avidity for CD58. Journal of immunology (Baltimore, Md. : 1950) 43 7681075
1989 Distribution and ontogeny of CD2 expression by murine T cells. Journal of immunology (Baltimore, Md. : 1950) 42 2565352
1993 CD2 expression on murine intestinal intraepithelial lymphocytes is bimodal and defines proliferative capacity. International immunology 41 8102249
1988 Exon-intron organization and sequence comparison of human and murine T11 (CD2) genes. Proceedings of the National Academy of Sciences of the United States of America 41 2894031
2009 Sequential cooperation of CD2 and CD48 in the buildup of the early TCR signalosome. Journal of immunology (Baltimore, Md. : 1950) 40 19494291
1993 Separable portions of the CD2 cytoplasmic domain involved in signaling and ligand avidity regulation. The Journal of experimental medicine 40 7901319
2006 Mechanisms of Cellular Avidity Regulation in CD2-CD58-Mediated T Cell Adhesion. ACS chemical biology 39 17168569
1993 T cell adhesion, avidity regulation and signaling: a molecular analysis of CD2. Seminars in immunology 39 7693022
2000 Ly108: a new member of the mouse CD2 family of cell surface proteins. Immunogenetics 38 11132158
1997 Cadmium (Cd2+) disrupts E-cadherin-dependent cell-cell junctions in MDCK cells. In vitro cellular & developmental biology. Animal 38 9282312
1994 Identification of a signaling complex involving CD2, zeta chain and p59fyn in T lymphocytes. European journal of immunology 38 7912674
1988 Evidence that protein kinase C differentially regulates the human T lymphocyte CD2 and CD3 surface antigens. European journal of immunology 38 2901966
1986 CD2 and CD3 antigens mobilize Ca2+ independently. European journal of immunology 37 3084290
2007 CD2 and TCR synergize for the activation of phospholipase Cgamma1/calcium pathway at the immunological synapse. International immunology 36 17220479
2010 The role of SLAM/CD2 polymorphisms in systemic autoimmunity. Current opinion in immunology 35 21094032
1990 Expression and ontogeny of CD2 on murine B cells. Journal of immunology (Baltimore, Md. : 1950) 34 1691222
2016 Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein-Protein Interaction. ACS chemical biology 33 27337048
1993 Alterations of CD2 association with T cell receptor signaling molecules in "CD2 unresponsive" human T lymphocytes. European journal of immunology 33 8093441
2000 A critical role for p59(fyn) in CD2-based signal transduction. European journal of immunology 32 11093170
1989 Expression and ontogeny of murine CD2. European journal of immunology 32 2569403
1989 CD2 expression in murine B cell lineage. International immunology 32 2577288
2001 p62dok negatively regulates CD2 signaling in Jurkat cells. Journal of immunology (Baltimore, Md. : 1950) 31 11254695
2018 CD2-Associated Protein Contributes to Hepatitis C, Virus Propagation and Steatosis by Disrupting Insulin Signaling. Hepatology (Baltimore, Md.) 30 29729186
2018 Costimulatory Function of Cd58/Cd2 Interaction in Adaptive Humoral Immunity in a Zebrafish Model. Frontiers in immunology 30 29904386
1998 Expression of CD2 on porcine B lymphocytes. Immunology 30 9824509
2016 MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform. Human mutation 29 26841241
2011 Conformationally constrained peptides from CD2 to modulate protein-protein interactions between CD2 and CD58. Journal of medicinal chemistry 29 21755948
2006 The CD2 family of natural killer cell receptors. Current topics in microbiology and immunology 29 16323413
2006 A large T cell invagination with CD2 enrichment resets receptor engagement in the immunological synapse. Journal of immunology (Baltimore, Md. : 1950) 29 16982875
2003 CD2 engagement induces dendritic cell activation: implications for immune surveillance and T-cell activation. Blood 29 12714509
2001 CD2- CD4+ CD56+ hematodermic/hematolymphoid malignancy. Journal of the American Academy of Dermatology 29 11174380
1989 Chromatin configuration of the human CD2 gene locus during T-cell development. Proceedings of the National Academy of Sciences of the United States of America 29 2567000
2006 Crystal structure and binding properties of the CD2 and CD244 (2B4)-binding protein, CD48. The Journal of biological chemistry 28 16803907
1991 Defective CD2 pathway T cell activation in systemic lupus erythematosus. Arthritis and rheumatism 28 1673843
1991 Regulation of T-cell differentiation by CD2 and CD28 accessory molecules. Immunology 28 1684171
2013 CD2-associated protein regulates plasmacytoid dendritic cell migration, but is dispensable for their development and cytokine production. Journal of immunology (Baltimore, Md. : 1950) 27 24218450
2020 Phosphoproteomics of CD2 signaling reveals AMPK-dependent regulation of lytic granule polarization in cytotoxic T cells. Science signaling 25 32398348
2012 Cd²⁺ block and permeation of CaV3.1 (α1G) T-type calcium channels: candidate mechanism for Cd²⁺ influx. Molecular pharmacology 25 22973059
2009 Inhibition and activation by CD244 depends on CD2 and phospholipase C-gamma1. The Journal of biological chemistry 25 19586919
1999 CD2 and CD3 associate independently with CD5 and differentially regulate signaling through CD5 in Jurkat T cells. Journal of immunology (Baltimore, Md. : 1950) 25 10510361
1998 Activation-induced NK cell death triggered by CD2 stimulation. European journal of immunology 25 9565369
1991 T cell receptor-independent CD2 signal transduction in FcR+ cells. The Journal of experimental medicine 25 1706751
2001 CD2-associated protein and the kidney. Current opinion in nephrology and hypertension 24 11195047
1992 Expression of the CD2 molecule on human B lymphoid progenitors. International immunology 24 1384685
1988 Immunoregulatory functions of paf-acether. II. Decrease of CD2 and CD3 antigen expression. European journal of immunology 23 2895712
2015 CD2-associated protein participates in podocyte apoptosis via PI3K/Akt signaling pathway. Journal of receptor and signal transduction research 22 26584949
2012 CD2 promotes human natural killer cell membrane nanotube formation. PloS one 22 23112830
2008 CD2-associated protein is widely expressed and differentially regulated during embryonic development. Differentiation; research in biological diversity 22 18177421
1988 Identification of CD2-/CD3+ T cells in fetal human tissue. The Journal of experimental medicine 22 2903216
1998 A p56lck-independent pathway of CD2 signaling involves Jun kinase. The Journal of biological chemistry 21 9727049

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