Affinage

CD28

T-cell-specific surface glycoprotein CD28 · UniProt P10747

Round 2 corrected
Length
220 aa
Mass
25.1 kDa
Annotated
2026-04-28
130 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD28 is the principal costimulatory receptor on T cells, integrating signals from B7 family ligands to amplify TCR-driven activation, promote survival, and shape metabolic and epigenetic programs that determine effector and memory T cell fate. Identified as a disulfide-bonded homodimeric immunoglobulin superfamily member, CD28 binds B7-1 (CD80), B7-2 (CD86), and—in humans—B7-H2 (ICOSL); upon ligand engagement and tyrosine phosphorylation of its cytoplasmic YMNM motif, it recruits PI3K (p85/p110), Grb2, and adaptors Vav1 and SLP-76 to activate PI3K–Akt signaling, boost PLCγ1/Ca²⁺/NFAT responses, inactivate GSK3, upregulate Bcl-xL for survival, drive glycolysis and early mitochondrial fatty acid oxidation essential for memory formation, and promote epigenetic remodeling of the IL-2 locus (PMID:8146197, PMID:7584133, PMID:12121659, PMID:28919076, PMID:15814687, PMID:8752911). Transmembrane-level regulation involves acidic phospholipid sequestration of the cytoplasmic domain, relieved by TCR-induced Ca²⁺, creating a dual positive-feedback circuit, while cis-B7:CD28 interactions at invaginated synaptic membranes on CD8⁺ T cells sustain costimulation via PI3K/SNX9/PKCθ to promote intratumoral T cell survival (PMID:29058713, PMID:37160118). Beyond conventional T cells, CD28 has a cell-intrinsic function in regulatory T cell homeostasis—Treg-specific CD28 deletion causes severe autoimmunity—and transduces pro-survival metabolic signaling in long-lived plasma cells through NF-κB/IRF4-dependent pathways (PMID:23281398, PMID:32579940).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1985 High

    Identification of CD28 (9.3 antigen) as a disulfide-bonded homodimeric T cell surface protein defining a costimulatory activation pathway independent of the TCR/CD3 complex resolved the question of whether T cell activation requires signals beyond the antigen receptor.

    Evidence Monoclonal antibody precipitation, co-modulation experiments, and T cell activation assays in primary human T cells

    PMID:3159820

    Open questions at the time
    • Ligand identity unknown
    • Signaling mechanism undefined
    • In vivo relevance not tested
  2. 1987 High

    Molecular cloning of CD28 cDNA established it as an immunoglobulin superfamily member and confirmed its homodimeric structure, enabling all subsequent structure-function studies.

    Evidence COS cell expression cloning with monoclonal antibody binding confirmation

    PMID:2825196

    Open questions at the time
    • Ligand still unidentified
    • Cytoplasmic signaling motifs not yet mapped
  3. 1991 High

    Identification of B7 (CD80) as the cognate CD28 ligand with measured binding affinity (~200 nM) established the receptor-ligand pair governing T cell costimulation and IL-2 production.

    Evidence Ig fusion protein binding assay, B7-transfected CHO cell costimulation, IL-2 transcript quantification

    PMID:1650475 PMID:1847722

    Open questions at the time
    • Possibility of additional ligands not excluded
    • Intracellular signaling pathway downstream of engagement unknown
  4. 1993 High

    Discovery of B7-2 (CD86) as a second CD28/CTLA-4 ligand and generation of CD28-knockout mice collectively demonstrated that CD28 is essential for robust IL-2 production and Ig class switching but that alternative costimulatory pathways exist.

    Evidence B7-2 cDNA cloning with CTLA4-Ig binding competition; CD28-KO mice with T cell activation, Ig, and infection phenotyping

    PMID:7688139 PMID:7694153

    Open questions at the time
    • Downstream signaling intermediates not molecularly defined
    • Mechanism of alternative costimulation unknown
  5. 1994 High

    Mapping PI3K recruitment to the phosphorylated YMNM motif in the CD28 cytoplasmic tail via p85 SH2 domains—with Y191 mutation abolishing both PI3K binding and IL-2 production—established the central signaling axis of CD28 costimulation.

    Evidence Site-directed mutagenesis, baculoviral p85 reconstitution, lipid kinase assay, co-immunoprecipitation in multiple labs

    PMID:8080844 PMID:8146197 PMID:8183372

    Open questions at the time
    • PI3K-independent CD28 functions not yet identified
    • Grb2 contribution not yet dissected from PI3K
  6. 1995 High

    Selective mutagenesis of the YMNM motif separated PI3K and Grb2 binding requirements, showing both are needed for full IL-2 induction and establishing that CD28 nucleates a multi-adaptor signaling complex.

    Evidence CD28 point mutants (Y191, M194) with selective PI3K/Grb2 disruption and IL-2 assay using B7-2-transfected cells

    PMID:7584133

    Open questions at the time
    • Downstream targets of Grb2 in CD28 pathway not defined
    • Role of additional adaptors (Vav, SLP-76) not yet tested
  7. 1996 High

    Demonstration that CD28 costimulation upregulates Bcl-xL to prevent T cell apoptosis identified the survival arm of CD28 signaling as mechanistically distinct from its proliferative arm.

    Evidence CD28-KO T cells with Bcl-xL/Bcl-2 expression analysis, apoptosis assays, ICE protease inhibition

    PMID:8752911

    Open questions at the time
    • Whether Bcl-xL induction requires PI3K or uses an independent pathway not resolved
    • Relationship to anergy prevention unclear
  8. 2000 High

    Genetic epistasis showed Cbl-b gates CD28 dependence by suppressing Vav activation; Cbl-b loss bypasses the CD28 requirement, placing Vav as a critical downstream node in CD28-dependent T cell activation.

    Evidence Cbl-b KO and Cbl-b/CD28 double-KO mice with Vav activation and IL-2 assays

    PMID:10646609

    Open questions at the time
    • Mechanism by which CD28 relieves Cbl-b suppression of Vav not defined
    • Quantitative contribution of Vav vs. PI3K not separated
  9. 2001 High

    A Y170F CD28 knockin mouse uncoupled PI3K/Grb2-dependent signals (Bcl-xL, survival) from PI3K-independent functions (anergy prevention, proliferation, IL-2), demonstrating that CD28 engages parallel signaling branches with separable biological outcomes.

    Evidence Transgenic knockin mouse expressing CD28-Y170F, T cell activation and anergy assays

    PMID:11276203

    Open questions at the time
    • Identity of the PI3K-independent signaling pathway not molecularly resolved
    • In vivo infection/autoimmune consequences not fully explored
  10. 2001 High

    CD28 was shown to amplify TCR signaling specifically at the PLCγ1/Ca²⁺ node (via Itk) without increasing proximal Zap-70 or LAT phosphorylation, defining the point of signal integration between TCR and CD28.

    Evidence Biochemical analysis of phospho-Zap70, phospho-LAT, PLCγ1 activation, and Ca²⁺ flux with Itk perturbation

    PMID:11754815

    Open questions at the time
    • How CD28 activates Itk at the molecular level not shown
    • Whether this applies to all T cell subsets unknown
  11. 2002 High

    Genomic and biochemical studies revealed that CD28 primarily amplifies CD3-initiated transcription rather than activating unique genes, with GSK3 inactivation promoting NFAT nuclear accumulation as a key mechanism, while CD28-PI3K-Akt drives glycolysis and glucose uptake to meet metabolic demands of activation.

    Evidence cDNA microarray, GSK3 phosphorylation assay, glucose uptake and glycolysis measurements with PI3K/Akt perturbation

    PMID:12121659 PMID:12195013

    Open questions at the time
    • Whether GSK3 inactivation is PI3K-dependent or PI3K-independent in this context not fully resolved
    • Metabolic requirements in different T cell subsets not compared
  12. 2002 High

    Biophysical characterization established that CD28 homodimers are monovalent for ligand binding whereas CTLA-4 is bivalent, with B7-2 preferentially binding CD28 over CTLA-4 relative to B7-1, explaining differential costimulatory versus inhibitory receptor engagement.

    Evidence Surface plasmon resonance and analytical ultracentrifugation

    PMID:12196291

    Open questions at the time
    • How monovalent binding translates to signaling threshold not modeled
    • In vivo kinetic competition between CD28 and CTLA-4 not measured
  13. 2005 High

    Crystal structure of CD28 confirmed the monovalent homodimer architecture and, combined with cryo-EM of mitogenic versus non-mitogenic antibody complexes, constrained models of receptor triggering geometry.

    Evidence X-ray crystallography and cryo-electron microscopy

    PMID:15696168

    Open questions at the time
    • No structure of CD28 bound to B7 ligands available
    • Transmembrane and cytoplasmic domain conformational changes not captured
  14. 2005 High

    CD28 costimulation was shown to induce stable epigenetic remodeling of the IL-2 locus (histone acetylation, CpG demethylation, chromatin opening), establishing that CD28 programs the epigenetic state distinguishing activated from anergic T cells.

    Evidence Chromatin accessibility, bisulfite sequencing, ChIP for histone marks in activated versus anergic T cells

    PMID:15814687

    Open questions at the time
    • Specific chromatin remodelers recruited by CD28 signaling not identified
    • Whether epigenetic effects are direct or secondary to transcription factor binding unclear
  15. 2005 High

    Discovery that CD28 engagement induces arginine methylation of Vav1, redirecting it to the nucleus, identified a novel post-translational modification linking CD28 to nuclear signaling.

    Evidence PRMT activity assay, arginine methylation detection, subcellular fractionation, transmethylation inhibitor

    PMID:16061726

    Open questions at the time
    • Which PRMT is responsible not identified
    • Nuclear function of methylated Vav1 not characterized
  16. 2011 High

    Identification of B7-H2 (ICOSL) as a third human CD28 ligand using a distinct binding site expanded the ligand repertoire and showed B7-H2:CD28 activates Akt/ERK and upregulates Bcl-xL.

    Evidence Receptor array, binding domain mapping, costimulation assays, signaling pathway analysis

    PMID:21530327

    Open questions at the time
    • Not conserved in mice, limiting genetic model validation
    • Physiological contexts where B7-H2:CD28 dominates over B7-1/B7-2 not defined
  17. 2013 High

    Treg-specific conditional CD28 deletion revealed a cell-intrinsic post-developmental role for CD28 in maintaining Treg homeostasis and suppressive function, with loss causing severe autoimmunity despite normal Treg numbers.

    Evidence Treg-specific CD28 conditional KO mice, flow cytometry, EAE model, complementation experiments

    PMID:23281398

    Open questions at the time
    • Downstream molecular program by which CD28 maintains Treg suppression not fully mapped
    • Whether CTLA-4 downregulation is cause or consequence of Treg failure unclear
  18. 2017 High

    NMR studies revealed that acidic phospholipids sequester the CD28 cytoplasmic domain at the membrane, with TCR-induced Ca²⁺ disrupting this interaction to liberate signaling motifs—establishing a membrane-level gating mechanism for CD28 activation.

    Evidence NMR spectroscopy of CD28 TM/cytoplasmic domain, lipid binding assays, Ca²⁺ perturbation, T cell signaling readouts

    PMID:29058713

    Open questions at the time
    • Whether lipid composition variations across T cell subsets modulate this gating is unknown
    • In vivo confirmation of the dual feedback circuit not yet achieved
  19. 2017 High

    CD28 was shown to transiently induce CPT1a before first division, priming mitochondrial fatty acid oxidation and spare respiratory capacity essential for memory T cell formation, with miR-33 attenuating this program in the absence of CD28.

    Evidence CD28-deficient T cells, CPT1a expression kinetics, miR-33/TXNIP analysis, mitochondrial imaging, spare respiratory capacity measurement

    PMID:28919076

    Open questions at the time
    • Signaling branch (PI3K vs. PI3K-independent) driving CPT1a induction not identified
    • Whether this metabolic priming applies to CD4⁺ T cells equally is unknown
  20. 2020 High

    CD28 was found to transduce pro-survival signals in long-lived plasma cells through SLP-76-dependent NF-κB activation driving IRF4 and a ROS-dependent metabolic program, extending CD28 function beyond T cells.

    Evidence LLPC vs. SLPC comparison, SLP76 expression, glucose uptake, mitochondrial/ROS assays, NF-κB and IRF4 measurement

    PMID:32579940

    Open questions at the time
    • CD28 ligand source in the bone marrow niche not defined
    • Whether plasma cell CD28 signaling uses the same YMNM-PI3K axis as T cells not tested
  21. 2023 High

    Discovery of cis-B7:CD28 interactions on CD8⁺ T cells at invaginated synaptic membranes—driven by PI3K and SNX9 and signaling through PKCθ—revealed a cell-autonomous costimulatory mechanism that sustains intratumoral T cell survival.

    Evidence Live cell imaging, co-IP, PI3K/SNX9 perturbation, PKCθ assay, T cell-specific B7 KO in mouse tumor models

    PMID:37160118

    Open questions at the time
    • Structural basis of cis vs. trans B7:CD28 interaction not resolved
    • Whether cis-signaling occurs in CD4⁺ T cells or Tregs unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the CD28–B7 ligand complex, the molecular identity of the PI3K-independent CD28 signaling branch that prevents anergy, the chromatin remodelers directly recruited by CD28 signaling, and how cis- versus trans-B7 engagement is regulated across immune cell types and tissue microenvironments.
  • No full-length CD28:B7 co-crystal structure exists
  • PI3K-independent anergy-prevention pathway molecularly uncharacterized
  • Tissue-specific regulation of cis-B7:CD28 not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 6
Pathway
R-HSA-168256 Immune System 13 R-HSA-162582 Signal Transduction 8 R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-4839726 Chromatin organization 1
Partners
CD80CD86GRB2ITKPIK3R1PRKCQSLP76VAV1

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 CD28 (Tp44) is a T-cell-specific homodimeric surface protein with homology to the immunoglobulin superfamily; its cDNA was cloned by transient COS cell expression, revealing it directs production of a disulfide-bonded homodimer. COS cell expression cloning, monoclonal antibody binding, molecular characterization Proceedings of the National Academy of Sciences of the United States of America High 2825196
1985 CD28 (9.3 antigen) is a disulfide-bonded dimer of a 44 kDa polypeptide that defines a novel T cell activation pathway independent of the T3/Ti complex, inducing IL-2 receptor expression and IL-2 secretion when crosslinked with TPA. Monoclonal antibody precipitation, co-modulation experiments, T cell activation assays The Journal of experimental medicine High 3159820
1991 CD28 is the primary receptor for B7 on T cells; B7-CD28 interaction (direct binding, Kd ~200 nM) costimulates T cell proliferation and specifically increases IL-2 mRNA accumulation. Ig fusion protein binding assay, B7-transfected CHO cell costimulation, IL-2 transcript measurement The Journal of experimental medicine High 1847722
1991 B7 ligation of CD28 on T cells induces proliferation and high-level IL-2 secretion; this response is specific and abrogated by anti-B7 antibody. B7-transfected CHO cell costimulation assay, antibody blockade, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America High 1650475
1993 B70 (B7-2/CD86) is a second ligand for CD28 and CTLA-4; monoclonal antibody to B70 inhibits CTLA4-Ig binding to B lymphoblastoid cells and blocks primary allogeneic MLR. cDNA cloning, CTLA4-Ig fusion protein binding inhibition, mixed lymphocyte reaction Nature High 7694153
1993 CD28-knockout mice have impaired lectin-stimulated IL-2 production and reduced IL-2 receptor alpha expression; CD28 is required for T helper cell activity and immunoglobulin class switching but not for all T cell responses, indicating alternative costimulatory pathways exist. Genetic knockout mouse, T cell activation assays, immunoglobulin measurement, infection models Science High 7688139
1993 CD28 receptor ligation induces tyrosine phosphorylation of specific substrates including phospholipase C gamma 1, and triggers both calcium-dependent and calcium-independent signals. Phosphorylation assays in activated T cells Annual review of immunology Medium 8386518
1994 PI3K (phosphatidylinositol 3-kinase) binds directly to the phosphorylated YMNM (Y191MXM) motif in the CD28 cytoplasmic tail via the SH2 domains of the p85 subunit; mutation of Y191 abolishes PI3K binding and CD28-mediated IL-2 production. Site-directed mutagenesis, baculoviral p85 reconstitution, lipid kinase assay, HPLC, peptide competition Proceedings of the National Academy of Sciences of the United States of America High 8146197
1994 CD28 becomes tyrosine-phosphorylated after B7.1/CD80 engagement, inducing complex formation with PI3K via the p85 SH2 domain at the Y173 (YXXM) motif; CD28 mutants lacking this site cannot stimulate IL-2 production. Tyrosine phosphorylation assay, co-immunoprecipitation, CD28 mutagenesis, IL-2 production assay Nature High 8183372
1994 CD28 associates with PI3K following CD28 cross-linking, and a synthetic peptide representing the YMNM motif from the CD28 cytoplasmic tail interacts with PI3K only when the tyrosine is phosphorylated. Co-immunoprecipitation in Jurkat cells, phosphopeptide binding assay International immunology Medium 8080844
1995 The CD28 pYMNM motif Y191 mutation disrupts both PI3K and Grb2 binding; M194 mutation disrupts only PI3K binding; both mutants fail to support IL-2 production upon B7-2 (CD86) engagement, directly implicating PI3K in CD28-mediated costimulation. CD28 point mutant expression, PI3K and Grb2 binding assays, IL-2 production assay with B7-2 transfected cells Immunity High 7584133
1996 CD28 costimulation upregulates Bcl-xL expression to enhance T cell survival during activation; CD28-deficient T cells show increased apoptosis that can be blocked by ICE protease inhibitors; this survival function is Fas-independent. CD28-KO mouse T cells, Bcl-xL/Bcl-2/Fas protein expression, apoptosis assays, lpr mouse comparison, ICE protease inhibitor treatment Journal of immunology High 8752911
2000 Cbl-b, an adaptor molecule, regulates the CD28 dependence of T cell activation; Cbl-b-deficient T cells do not require CD28 engagement for IL-2 production. Cbl-b selectively suppresses TCR-mediated Vav activation, and Cbl-b loss enhances Vav (GEF for Rac1/Rho/CDC42) activation. Cbl-b knockout mice, IL-2 production assay, genetic epistasis with CD28-KO mice, Vav activation assay Nature High 10646609
2001 CD28 costimulation prevents anergy and promotes T cell proliferation via a PI3K-independent pathway; a Y170F point mutation in CD28 uncouples SH2-dependent signaling (PI3K/Grb2/Gads) from CD28, abolishing Bcl-xL upregulation and survival but preserving anergy prevention, proliferation, IL-2 secretion, and B cell help. Transgenic knockin mouse expressing CD28-Y170F mutant, T cell activation assays, Bcl-xL expression, anergy assessment Nature immunology High 11276203
2001 SIV and HIV-1 Nef proteins downmodulate CD28 by accelerating its endocytosis via the AP-2 clathrin adaptor pathway; Nef, AP-2, and CD28 form a ternary complex involving the membrane-proximal CD28 cytoplasmic domain, and Nef mutations disrupting AP-2 interaction abrogate CD28 downregulation. Nef-GFP fusion protein co-localization, co-immunoprecipitation with AP-2, endocytosis assay, Nef mutagenesis The EMBO journal High 11285224
2001 CD28 amplifies TCR signaling by enhancing T cell–APC contacts and specifically boosting PLCgamma1 activation and Ca2+ response downstream of TCR, without increasing Zap-70 or LAT phosphorylation; the PTK Itk controls the PLCgamma1 amplification function. Biochemical analysis of signaling intermediates (phospho-Zap70, phospho-LAT, PLCgamma1 activation, Ca2+ flux), Itk involvement assay Immunity High 11754815
2001 TNF-alpha directly suppresses CD28 gene transcription by inhibiting activity of the CD28 minimal promoter through reduction of DNA-protein complex formation at initiator sequence motifs (sites alpha and beta), as shown by reporter gene assays and in vitro transcription assays. Reporter gene bioassay, in vitro transcription assay, EMSA (DNA-protein complex formation), nuclear extract analysis Journal of immunology High 11544310
2002 CD28 signaling through PI3K and Akt is required for T cells to increase glycolytic rate and glucose uptake upon activation; CD28 costimulation drives glycolytic flux in excess of immediate ATP/ADP needs, preparing cells for sustained metabolic demands. Glucose uptake assays, glycolysis measurements, PI3K/Akt inhibitor treatment, CD28-deficient T cell comparison Immunity High 12121659
2002 Lck undergoes autophosphorylation in the immunological synapse when T cells encounter APCs; CD4 recruits Lck to the T cell–APC interface, whereas CD28 sustains Lck activation; TCR cross-linking alone cannot stimulate Lck autophosphorylation. Phosphospecific anti-Lck antiserum, APC stimulation, CD4 and CD28 perturbation, immunofluorescence Nature immunology High 11828322
2001 CD28 co-localizes with protein kinase C theta (PKCtheta) within TCR-CD28 microclusters at the immunological synapse, and this association promotes sustained T cell signaling from a specialized subregion of the IS after mature synapse formation. Live cell imaging, microcluster analysis, immunological synapse imaging Immunological reviews Medium 19426213
2004 Soluble CD28 signals through B7-1 (CD80) and B7-2 (CD86) on dendritic cells to induce IL-6 and IFN-gamma production; IL-6 production requires CD80, CD86, and p38 MAPK and prevents IFN-gamma-driven immunosuppressive tryptophan catabolism, demonstrating reverse (inside-out) B7 signaling. Soluble CD28 treatment of DCs, cytokine measurement, p38 MAPK inhibition, in vivo adjuvant assays Nature immunology High 15467723
2005 Crystal structure of soluble CD28 in complex with a mitogenic antibody Fab fragment reveals CD28 is a monovalent homodimer, redefining evolutionary relationships within the CD28/CTLA-4 superfamily and accounting for distinct ligand-binding and stoichiometric properties versus CTLA-4; cryo-EM comparisons of mitogenic vs. non-mitogenic antibody complexes constrain receptor-triggering models. X-ray crystallography, cryo-electron microscopy Nature immunology High 15696168
2002 B7-1 and B7-2 differ in affinity and structure: B7-2 binds CD28 and CTLA-4 more weakly than B7-1; relative to CTLA-4 binding, B7-2 binds CD28 2–3-fold more effectively than B7-1; B7-1 is bivalent (self-associates) while B7-2 does not; CD28 homodimers are monovalent whereas CTLA-4 homodimers are bivalent. Surface plasmon resonance, analytical ultracentrifugation, structural comparison Immunity High 12196291
2005 CD28 costimulation induces stable epigenetic modification of the IL-2 locus: histone acetylation, cytosine demethylation, and chromatin remodeling to an accessible state; TCR activation without CD28 fails to promote these epigenetic changes, leaving the IL-2 promoter inaccessible in anergic cells. Chromatin accessibility assay, bisulfite sequencing (cytosine methylation), ChIP (histone acetylation), comparison of activated vs. anergic T cells Journal of immunology High 15814687
2005 CD28 engagement induces protein arginine methyltransferase activity and arginine methylation of several proteins including Vav1; methylated Vav1 localizes selectively to the nucleus; inhibiting transmethylation reduces Vav1 methylation and IL-2 production. Protein arginine methyltransferase activity assay, arginine methylation detection, subcellular fractionation, pharmacological inhibition of S-adenosyl-L-homocysteine hydrolase The Journal of experimental medicine High 16061726
2009 p85beta (regulatory subunit of PI3K) binds to CD28 and to CBL with greater affinity than p85alpha; deletion of p85beta impairs CD28-induced c-CBL and CBL-b downregulation and PI3K pathway activation, resulting in defective T cell differentiation and failure of secondary immune response. p85beta-KO mice, co-immunoprecipitation, PI3K activation assay, CBL expression measurement, secondary immune response assay Blood High 19190244
2002 Genomic analysis shows CD28 agonists alone induce few gene expression changes; the principal effect of CD28 costimulation is amplification of the CD3 transcriptional response; CD28 promotes phosphorylation/inactivation of GSK3 (NFAT nuclear export kinase), enhancing nuclear NFAT accumulation and NFAT target gene expression. cDNA microarray, GSK3 phosphorylation assay, NFAT dephosphorylation assay, FK506 (calcineurin inhibitor) treatment Proceedings of the National Academy of Sciences of the United States of America High 12195013
2011 B7-H2 (ICOSL) functions as a ligand for CD28 and CTLA-4 in humans (but not mice); B7-H2–CD28 interaction uses a distinct binding domain from B7-1/B7-2; B7-H2 costimulation via CD28 induces Bcl-xL, downregulates p27(kip1), and activates ERK and AKT signaling pathways. Receptor array assay, binding domain mapping, T cell costimulation assays, signaling pathway analysis (ERK, AKT phosphorylation), Bcl-xL and p27 expression Immunity High 21530327
2013 CD28 has an obligate cell-intrinsic function in Tregs beyond thymic development; Treg-specific Cd28 conditional knockout mice develop severe autoimmunity despite normal FOXP3+ cell numbers; CD28 loss in Tregs dampens CTLA-4, PD-1, and CCR6 expression and confers a proliferative/survival disadvantage in competitive environments. Treg-specific conditional CD28 knockout mice, flow cytometry, in vivo autoimmune models (EAE), Treg complementation experiments The Journal of clinical investigation High 23281398
2014 CD28 and CD3 provide complementary functions in T cell force generation: force generation is associated with CD3/TCR complex engagement, while CD28 increases traction forces associated with CD3 through the PI3K signaling pathway rather than by direct cell-substrate coupling; phosphorylated Pyk2 is concentrated at sites of force generation. Traction force microscopy on elastomer pillar arrays, PI3K inhibitor treatment, phospho-Pyk2 localization Proceedings of the National Academy of Sciences of the United States of America High 24469820
2016 Bacterial superantigens bind both B7-2 and CD28 at their homodimer interfaces using the same 12-aa domain, potently enhancing B7-2/CD28 avidity and inducing T cell hyperactivation; short B7-2 dimer interface mimetic peptides prevent superantigen binding and protect mice from lethal challenge. Binding assays, B7-2 and CD28 homodimer interface mutagenesis, cytokine production assays, mouse lethality model Proceedings of the National Academy of Sciences of the United States of America High 27708164
2017 CD28 conformation and signaling are regulated by two counteractive charged factors: acidic phospholipids sequester CD28 cytoplasmic signaling motifs within the membrane (limiting basal signaling), while TCR-induced local Ca2+ increase directly disrupts CD28-lipid interaction, releasing the cytoplasmic domain for signaling; TCR, Ca2+, and CD28 form a dual-positive-feedback circuit amplifying T cell signaling. NMR spectroscopy of CD28 transmembrane/cytoplasmic domain, lipid binding assays, Ca2+ perturbation experiments, T cell signaling assays Nature structural & molecular biology High 29058713
2017 CD28 transiently promotes expression of CPT1a (carnitine palmitoyltransferase 1a) before the first cell division, facilitating mitochondrial fatty acid oxidation, cristae remodeling, and enhanced spare respiratory capacity; miR-33 (targeted by TXNIP) attenuates Cpt1a in the absence of CD28; early CD28-dependent mitochondrial priming is essential for memory T cell formation. CD28-deficient T cells, Cpt1a expression measurement, miR-33 and TXNIP analysis, mitochondrial imaging, spare respiratory capacity assay, cytokine production upon restimulation Cell High 28919076
2016 CTLA4-CD28 gene fusion (encoding CTLA4 extracellular domain fused to CD28 cytoplasmic domain) is frequently found in angioimmunoblastic T-cell lymphoma (58%), PTCL-NOS (23%), and extranodal NK/T-cell lymphoma (29%); ectopic expression in Jurkat/H9 cells enhances proliferation and activates AKT and ERK downstream of what would normally be an inhibitory CTLA4 signal. RNA sequencing, RT-PCR/Sanger sequencing, ectopic expression in T cell lines, AKT/ERK phosphorylation assay Haematologica High 26819049
2021 CARs containing the CD28 transmembrane domain (TMD) heterodimerize with endogenous CD28 in human T cells via polar amino acids in the CD28-TMD; this heterodimerization reduces CD28 cell-surface expression and does not respond to CD80/CD86 stimulation, revealing a fundamental functional difference from CD8-TMD CARs. Co-immunoprecipitation, CAR-dependent proliferation assay upon anti-CD28 stimulation, CD28-TMD mutagenesis, flow cytometry Frontiers in immunology High 33833759
2023 CD8+ T cells display B7 ligands (CD80/CD86) that interact with CD28 in cis at invaginated synaptic membranes; this cis-B7:CD28 interaction is driven by PI3K and sorting nexin-9 (SNX9), triggers CD28 signaling through PKCtheta, and promotes CD8+ T cell survival, migration, and cytokine production; loss of cis-B7:CD28 interactions in mouse tumor models decreases intratumoral T cells and accelerates tumor growth. Live cell imaging, co-IP, PI3K and SNX9 perturbation, PKCtheta signaling assay, mouse tumor models with T cell-specific B7 knockout Immunity High 37160118
2020 CD28 transduces pro-survival signaling in long-lived plasma cells (LLPCs) specifically through differential SLP76 expression; CD28 signaling in LLPCs increases glucose uptake, mitochondrial mass/respiration, and ROS production; CD28-mediated NF-κB activation and survival are ROS-dependent; IRF4 (NF-κB target) upregulated by CD28 mediates this metabolic program. LLPC vs. SLPC comparison, SLP76 expression analysis, glucose uptake, mitochondrial assays, ROS measurement, NF-κB activation assay, IRF4 expression Cell reports High 32579940
2024 CD28 costimulatory domain incorporated into CAR-NK cells recruits LCK and ZAP70 kinases to the CD3ζ signaling complex, initiating a signaling cascade that enhances CAR-NK cell antitumor persistence and cytotoxicity. CAR-NK cell engineering, kinase recruitment assay, in vitro cytotoxicity assay, multiple xenograft mouse models Cancer discovery High 38900051
1997 Itk negatively regulates CD28-mediated T cell proliferation: Itk-deficient T cells show augmented proliferative response to CD28 costimulation (calcineurin-independent) without increased IL-2, establishing that Itk plays distinct inhibitory roles in CD28 versus CD3 signaling pathways. Itk-knockout mice, T cell proliferation assay, IL-2 measurement, calcineurin pathway inhibition The Journal of experimental medicine High 9221751
2000 CD28 can activate PI3K and cooperate with adapters Vav and SLP-76 to induce IL-2 and IL-4 transcription independently of TCR ligation, providing a molecular basis for in trans costimulation. CD28 stimulation without TCR ligation, IL-2/IL-4 promoter assays, Vav and SLP-76 co-signaling analysis Immunological reviews Medium 12670393
2000 Unexpectedly, the Y189F CD28 YMNM mutant that disrupts PI3K binding shows reduced but significant IL-2 promoter activity, while N191A (retains PI3K binding) completely abrogates activity; PI3K inhibitor augments IL-2 promoter activity while constitutively active PI3K reduces it, suggesting PI3K acts as a negative mediator of CD28-mediated IL-2 transcription. CD28 YMNM point/deletion mutant expression in Jurkat, IL-2 promoter reporter assay, PI3K pharmacological inhibitor, constitutively active PI3K overexpression The Journal of biological chemistry Medium 11113113
2013 CD28 co-stimulatory pathway, specifically through the Tec-family kinase ITK, regulates trafficking of autoreactive T cells to tissues; ablation of ITK in Ctla4−/− mice blocks tissue infiltration without preventing lymphoid organ T cell activation; ITK inhibitors phenocopy ITK null and prevent islet infiltration in diabetes models. Double-KO mice (Itk−/−;Ctla4−/−), T cell trafficking analysis, ITK pharmacological inhibition, pancreatic islet infiltration model Nature medicine High 24270545
2016 CD28 costimulation drives distinct metabolic programs in CAR T cells: CD28 signaling domains favor effector memory differentiation with a glycolytic gene signature, while 4-1BB domains promote central memory with enhanced fatty acid oxidation and mitochondrial biogenesis. Metabolic flux analysis, gene expression profiling, mitochondrial assays in CAR T cells with different costimulatory domains Immunity High 26885860

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature reviews. Immunology 2399 23470321
1996 CD28/B7 system of T cell costimulation. Annual review of immunology 2082 8717514
2013 Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 1778 24390342
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2002 The B7-CD28 superfamily. Nature reviews. Immunology 1333 11910893
1994 The B7 and CD28 receptor families. Immunology today 1282 7522010
1993 The role of the CD28 receptor during T cell responses to antigen. Annual review of immunology 1250 8386518
1991 Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. The Journal of experimental medicine 1219 1847722
2002 The CD28 signaling pathway regulates glucose metabolism. Immunity 1181 12121659
1993 Differential T cell costimulatory requirements in CD28-deficient mice. Science (New York, N.Y.) 1050 7688139
2016 Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity 923 26885860
1993 B70 antigen is a second ligand for CTLA-4 and CD28. Nature 918 7694153
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
1987 Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proceedings of the National Academy of Sciences of the United States of America 858 2825196
2011 CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. The Journal of clinical investigation 849 21540550
2002 Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nature biotechnology 817 11753365
2010 Multiple common variants for celiac disease influencing immune gene expression. Nature genetics 801 20190752
2016 CD28 Costimulation: From Mechanism to Therapy. Immunity 726 27192564
2009 Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proceedings of the National Academy of Sciences of the United States of America 719 19211796
1990 Role of the CD28 receptor in T-cell activation. Immunology today 714 2162180
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2001 T-cell regulation by CD28 and CTLA-4. Nature reviews. Immunology 684 11905831
2009 CD28 and CTLA-4 coreceptor expression and signal transduction. Immunological reviews 681 19426212
1995 Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence. Nature 660 7566098
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 The interaction properties of costimulatory molecules revisited. Immunity 524 12196291
1991 B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proceedings of the National Academy of Sciences of the United States of America 515 1650475
2000 Cbl-b regulates the CD28 dependence of T-cell activation. Nature 496 10646609
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2003 The role of PI3K in immune cells. Nature immunology 391 12660731
1993 CD28- T lymphocytes. Antigenic and functional properties. Journal of immunology (Baltimore, Md. : 1950) 367 8381831
1985 Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen). The Journal of experimental medicine 362 3159820
1998 CD28/B7 costimulation: a review. Critical reviews in immunology 351 9784967
1994 Binding of phosphatidylinositol-3-OH kinase to CD28 is required for T-cell signalling. Nature 345 8183372
1994 Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. The Journal of experimental medicine 343 7516408
2011 Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family. Immunological reviews 311 21488898
1992 Identification and distribution of the costimulatory receptor CD28 in the mouse. Journal of immunology (Baltimore, Md. : 1950) 311 1320641
1993 Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation. Science (New York, N.Y.) 297 8484124
1994 CD28-B7 interactions in T-cell activation. Current opinion in immunology 287 7522466
2003 Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nature reviews. Immunology 285 12876557
2009 Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nature genetics 284 19898481
2001 Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Nature 269 11279501
1994 T-cell antigen CD28 interacts with the lipid kinase phosphatidylinositol 3-kinase by a cytoplasmic Tyr(P)-Met-Xaa-Met motif. Proceedings of the National Academy of Sciences of the United States of America 265 8146197
1997 Lck regulates Vav activation of members of the Rho family of GTPases. Molecular and cellular biology 264 9032261
1997 Costimulation of CD28- T lymphocytes by 4-1BB ligand. Journal of immunology (Baltimore, Md. : 1950) 252 8992967
2001 Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule. Journal of immunology (Baltimore, Md. : 1950) 251 11714771
2010 Immune evasion and counteraction of restriction factors by HIV-1 and other primate lentiviruses. Cell host & microbe 250 20638642
2002 Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proceedings of the National Academy of Sciences of the United States of America 243 12195013
2017 Mitochondrial Priming by CD28. Cell 241 28919076
1999 T cell co-stimulatory molecules other than CD28. Current opinion in immunology 236 10375549
2004 CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86. Nature immunology 223 15467723
2001 The immunological synapse and CD28-CD80 interactions. Nature immunology 222 11713465
2001 Down-regulation of CD28 expression by TNF-alpha. Journal of immunology (Baltimore, Md. : 1950) 216 11544310
2010 An enigmatic tail of CD28 signaling. Cold Spring Harbor perspectives in biology 213 20534709
1996 CD28 costimulation prevents cell death during primary T cell activation. Journal of immunology (Baltimore, Md. : 1950) 205 8752911
2014 CD28 and CD3 have complementary roles in T-cell traction forces. Proceedings of the National Academy of Sciences of the United States of America 202 24469820
2007 CD8+ CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. Journal of immunology (Baltimore, Md. : 1950) 184 17878327
2013 An obligate cell-intrinsic function for CD28 in Tregs. The Journal of clinical investigation 182 23281398
2001 Mechanism for down-regulation of CD28 by Nef. The EMBO journal 169 11285224
2019 The Evolving Role of CD8+CD28- Immunosenescent T Cells in Cancer Immunology. International journal of molecular sciences 162 31181772
2002 Regulation of Lck activity by CD4 and CD28 in the immunological synapse. Nature immunology 157 11828322
2005 Crystal structure of a soluble CD28-Fab complex. Nature immunology 156 15696168
2001 A point mutation in CD28 distinguishes proliferative signals from survival signals. Nature immunology 152 11276203
1999 Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. Journal of immunology (Baltimore, Md. : 1950) 147 10352273
2009 The clinical utility of inhibiting CD28-mediated costimulation. Immunological reviews 138 19426230
2001 CD28 as a molecular amplifier extending TCR ligation and signaling capabilities. Immunity 129 11754815
2015 CD28 co-stimulation in T-cell homeostasis: a recent perspective. ImmunoTargets and therapy 127 27471717
2011 B7-h2 is a costimulatory ligand for CD28 in human. Immunity 125 21530327
1995 CD28 and apoptosis. Current opinion in immunology 123 8573303
1995 CD43 is a murine T cell costimulatory receptor that functions independently of CD28. The Journal of experimental medicine 121 7790813
1995 Selective CD28pYMNM mutations implicate phosphatidylinositol 3-kinase in CD86-CD28-mediated costimulation. Immunity 118 7584133
1996 CD28: a signalling perspective. The Biochemical journal 113 8809021
2003 Restoration of CD28 expression in CD28- CD8+ memory effector T cells reconstitutes antigen-induced IL-2 production. The Journal of experimental medicine 108 12963692
2005 The B7/CD28 costimulatory family in autoimmunity. Immunological reviews 107 15790355
2015 HHLA2 and TMIGD2: new immunotherapeutic targets of the B7 and CD28 families. Oncoimmunology 103 26405587
2002 CD28 function: a balance of costimulatory and regulatory signals. Journal of clinical immunology 100 11958588
1996 The repertoire of CD4+ CD28- T cells in rheumatoid arthritis. Molecular medicine (Cambridge, Mass.) 99 8898376
2021 The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28. Frontiers in immunology 98 33833759
2005 Signals from CD28 induce stable epigenetic modification of the IL-2 promoter. Journal of immunology (Baltimore, Md. : 1950) 98 15814687
1994 CD28 of T lymphocytes associates with phosphatidylinositol 3-kinase. International immunology 96 8080844
2024 The B7:CD28 family and friends: Unraveling coinhibitory interactions. Immunity 86 38354702
2005 CD28 costimulatory signal induces protein arginine methylation in T cells. The Journal of experimental medicine 83 16061726
2004 Critical role of OX40 in CD28 and CD154-independent rejection. Journal of immunology (Baltimore, Md. : 1950) 83 14734751
1993 Expansion of a CD8+CD28- cell population in the blood and lung of HIV-positive patients. Journal of acquired immune deficiency syndromes 79 8229654
2009 Dynamic regulation of T-cell costimulation through TCR-CD28 microclusters. Immunological reviews 78 19426213
1996 Chagasic patients lack CD28 expression on many of their circulating T lymphocytes. Scandinavian journal of immunology 77 8560201
2016 Costimulation Blockade in Autoimmunity and Transplantation: The CD28 Pathway. Journal of immunology (Baltimore, Md. : 1950) 75 27591335
2004 Elevated pro-inflammatory CD4+CD28- lymphocytes and stroke recurrence and death. Neurology 75 15505163
2015 The story of CD4+ CD28- T cells revisited: solved or still ongoing? Journal of immunology research 69 25834833
2002 CD8+CD28- T cells: certainties and uncertainties of a prevalent human T-cell subset. Immunology and cell biology 67 11869357
2018 Programmed cell death protein 1 activation preferentially inhibits CD28.CAR-T cells. Cytotherapy 66 30309710
2016 Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma. Haematologica 63 26819049
2010 Activating NK-cell receptors co-stimulate CD4(+)CD28(-) T cells in patients with rheumatoid arthritis. European journal of immunology 59 19904767
2021 CD28.OX40 co-stimulatory combination is associated with long in vivo persistence and high activity of CAR.CD30 T-cells. Haematologica 58 32381575
2011 Regulation of NF-κB induction by TCR/CD28. Immunologic research 57 21717079
2006 CD28 and ICOS: similar or separate costimulators of T cells? Immunology letters 57 16580736
2000 Coordinate regulation of T cell activation by CD2 and CD28. Journal of immunology (Baltimore, Md. : 1950) 57 10725714
1996 Regulation of T cell activation by CD28 and CTLA4. Advances in experimental medicine and biology 57 8910687
2023 cis-B7:CD28 interactions at invaginated synaptic membranes provide CD28 co-stimulation and promote CD8+ T cell function and anti-tumor immunity. Immunity 56 37160118
2017 CD28- and CD28lowCD8+ Regulatory T Cells: Of Mice and Men. Frontiers in immunology 54 28167946
2017 Dynamic regulation of CD28 conformation and signaling by charged lipids and ions. Nature structural & molecular biology 53 29058713
2000 CD3zeta and CD28 down-modulation on CD8 T cells during viral infection. Blood 53 10910918
1996 Interactions of CD80 and CD86 with CD28 and CTLA4. Journal of immunology (Baltimore, Md. : 1950) 53 8609386
2003 Costimulation of human CD28- T cells by 4-1BB ligand. European journal of immunology 52 12645943
1996 The enigma of CD57+CD28- T cell expansion--anergy or activation? Clinical and experimental immunology 51 8603525
1994 Expression of CD28 on CD8+ and CD4+ lymphocytes during HIV infection. Scandinavian journal of immunology 50 7973455
2016 Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction. Proceedings of the National Academy of Sciences of the United States of America 48 27708164
1998 Contribution of CD4+, CD8+CD28+, and CD8+CD28- T cells to CD3+ lymphocyte homeostasis during the natural course of HIV-1 infection. The Journal of clinical investigation 47 9421475
2005 CD28 superagonists: mode of action and therapeutic potential. Immunology letters 45 16054703
2019 The CD28-B7 Family of Co-signaling Molecules. Advances in experimental medicine and biology 44 31758530
2010 A more selective costimulatory blockade of the CD28-B7 pathway. Transplant international : official journal of the European Society for Organ Transplantation 44 20964725
2002 Suppression of experimental autoimmune encephalomyelitis using peptide mimics of CD28. Journal of immunology (Baltimore, Md. : 1950) 43 12165548
2024 CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis. Cancer discovery 42 38900051
2020 CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival. Cell reports 41 32579940
2000 Novel role of phosphatidylinositol 3-kinase in CD28-mediated costimulation. The Journal of biological chemistry 40 11113113
1997 Itk negatively regulates induction of T cell proliferation by CD28 costimulation. The Journal of experimental medicine 39 9221751
2017 Membrane Rafts in T Cell Activation: A Spotlight on CD28 Costimulation. Frontiers in immunology 38 29163534
2013 CD28 and ITK signals regulate autoreactive T cell trafficking. Nature medicine 36 24270545
1992 CTLA-4 and CD28: similar proteins, neighbouring genes. International journal of cancer. Supplement = Journal international du cancer. Supplement 36 1330947
2013 Cross talk between CD3 and CD28 is spatially modulated by protein lateral mobility. Molecular and cellular biology 35 24379441
2009 Decreased ERK and JNK signaling contribute to gene overexpression in "senescent" CD4+CD28- T cells through epigenetic mechanisms. Journal of leukocyte biology 35 19843577
1996 Induction of autoimmunity in the absence of CD28 costimulation. Journal of immunology (Baltimore, Md. : 1950) 35 8759765
2014 A transendocytosis perspective on the CD28/CTLA-4 pathway. Advances in immunology 34 25175774
2003 Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation. Immunological reviews 34 12670393
1995 CD28:B7 interactions promote T cell adhesion. European journal of immunology 34 7489747
2009 p85beta phosphoinositide 3-kinase regulates CD28 coreceptor function. Blood 33 19190244
1997 The CD28-B7 costimulatory pathway and its role in autoimmune disease. Journal of leukocyte biology 33 9261329
2022 Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency. The Journal of experimental medicine 32 36515678
2017 Divide, Conquer, and Sense: CD8+CD28- T Cells in Perspective. Frontiers in immunology 32 28096804