Affinage

CD28

T-cell-specific surface glycoprotein CD28 · UniProt P10747

Length
220 aa
Mass
25.1 kDa
Annotated
2026-06-09
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD28 is the principal costimulatory receptor of T cells, a homodimer that lowers the threshold for activation by acting at the earliest steps of TCR signaling—its engagement is required for normal tyrosine phosphorylation of the TCR zeta chain and ZAP-70 and for downstream Ca2+/calcineurin, ERK/MAPK and JNK signaling (PMID:9692882), and CD28-deficient mice show defective IL-2 production, IL-2 receptor alpha expression, and immunoglobulin class switching while retaining cytotoxic responses (PMID:7688139). The receptor accumulates at the immature immunological synapse together with the TCR, where it forms TCR-CD28 microclusters that associate with PKCθ and sustain signaling at a discrete synapse subregion (PMID:15128767, PMID:19426213); productive costimulation requires spatial co-proximity of CD3 and CD28 ligands, governed by actin-constrained transport of active Lck (PMID:24379441). Costimulatory output is gated at the membrane itself: acidic phospholipids sequester the CD28 cytoplasmic signaling motifs, and TCR-induced Ca2+ disrupts this lipid interaction to release them, creating a dual positive-feedback amplification circuit with the TCR (PMID:29058713). Signal transduction proceeds through the YMNM motif at tyrosine 170/173, which recruits SH2-domain partners including PI3K and Grb2; mutation of this tyrosine uncouples Bcl-xL-dependent survival from the proliferative and IL-2-promoting outputs of CD28 (PMID:11276203), and CD28 cooperates with Vav and SLP-76, with Cbl-b suppression of Vav activation explaining the CD28-dependence of T cell activation (PMID:10646609, PMID:12670393). Through PI3K/Akt, CD28 drives metabolic reprogramming—increasing glycolysis and glucose uptake beyond immediate energetic need (PMID:12121659) and transiently inducing Cpt1a to prime mitochondrial fatty acid oxidation and spare respiratory capacity essential for protective memory (PMID:28919076). At the organismal level CD28 is required for germinal center formation and somatic hypermutation (PMID:8648099), exerts a cell-intrinsic function maintaining Foxp3+ Treg fitness and identity (PMID:23281398), and suppresses Th17 differentiation via IL-2/IFN-γ (PMID:19333372). Human CD28 is engaged not only by B7-1/B7-2 but also by B7-H2 (ICOSL), which costimulates primary and memory responses through Bcl-xL induction and ERK/AKT signaling (PMID:21530327). Crystallographic analysis defines CD28 as a monovalent homodimer distinct in ligand-binding and stoichiometry from the higher-affinity inhibitory relative CTLA-4 (PMID:8386518, PMID:15696168).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1993 Medium

    Established CD28 as a costimulatory receptor whose B7 engagement triggers tyrosine phosphorylation cascades, and positioned it against the structurally related, higher-affinity CTLA-4.

    Evidence Biochemical phosphorylation and binding-affinity assays summarized from primary studies

    PMID:8386518

    Open questions at the time
    • Did not map the specific cytoplasmic motifs responsible for partner recruitment
    • Affinity comparison did not resolve functional consequences of CTLA-4 vs CD28 binding
  2. 1993 High

    Genetic loss-of-function showed CD28 is required for IL-2 production, IL-2Rα expression and class switching but dispensable for cytotoxic T cell induction, defining the scope and limits of its in vivo role.

    Evidence CD28 knockout mice with T cell functional and immunoglobulin assays

    PMID:7688139

    Open questions at the time
    • Did not identify the molecular signals downstream of CD28 underlying these phenotypes
    • Could not separate proliferation from survival contributions
  3. 1996 High

    Identified Bcl-xL upregulation as a discrete CD28 survival output independent of Bcl-2 and Fas, explaining how costimulation protects activated T cells from apoptosis.

    Evidence CD28-KO mice plus CTLA4Ig blockade with Bcl-xL/Bcl-2/Fas western blots and ICE-protease readouts

    PMID:8752911

    Open questions at the time
    • Did not link Bcl-xL induction to a specific cytoplasmic signaling motif
    • Mechanism connecting CD28 to Bcl-xL transcription unresolved at this stage
  4. 1996 High

    Demonstrated CD28 is required for germinal center formation and somatic hypermutation, defining its role in T-dependent humoral responses.

    Evidence CD28-KO mice with lymphoid histology and B cell response analysis

    PMID:8648099

    Open questions at the time
    • Did not distinguish T-cell-intrinsic from indirect contributions to GC formation
    • Downstream signaling requirements not addressed
  5. 1998 Medium

    Showed CD28 acts on the earliest TCR signaling events under physiological antigen presentation, placing costimulation upstream rather than parallel to proximal TCR signaling.

    Evidence Antigen/superantigen stimulation on B7+ APCs with anti-CD28 blockade and phospho-blots in Jurkat and primary T cells

    PMID:9692882

    Open questions at the time
    • Single-lab two-cell-system study
    • Did not define the biochemical bridge from CD28 to TCR zeta/ZAP-70 phosphorylation
  6. 2000 High

    Epistasis placed Cbl-b suppression of Vav activation as the basis for CD28-dependence, showing CD28 functions to relieve a negative checkpoint on TCR signaling.

    Evidence Cbl-b x CD28 double-KO mice with IL-2, Vav activation and signaling-intermediate assays

    PMID:10646609

    Open questions at the time
    • Did not establish direct CD28 engagement of Vav/Cbl-b
    • Left open how CD28 itself amplifies Vav signaling
  7. 2000 Medium

    Linked CD28 to PI3K, Vav and SLP-76 cooperation for IL-2/IL-4 transcription, providing a molecular basis for in-trans costimulation, and probed whether YMNM-associated PI3K is positive or negative for IL-2.

    Evidence CD28 point/deletion mutants with IL-2 promoter reporters and PI3K manipulation in Jurkat cells (with review summary)

    PMID:11113113 PMID:12670393

    Open questions at the time
    • Reporter-based and partly review-derived; in vivo relevance of negative PI3K role unresolved
    • Conflicting positive vs negative roles for YMNM-associated PI3K not reconciled
  8. 2001 High

    Knockin mutation of the YMNM tyrosine separated the SH2-dependent survival arm (Bcl-xL induction) from the proliferative/IL-2/anergy-prevention arm, demonstrating CD28 has genetically separable signaling outputs.

    Evidence Y170F CD28 knockin mice with survival, proliferation and IL-2 readouts

    PMID:11276203

    Open questions at the time
    • Did not identify which SH2 partner mediates the survival arm in vivo
    • Mechanism of the tyrosine-independent proliferative arm unresolved
  9. 2001 Medium

    Identified transcriptional control of CD28 itself, showing TNF-α represses CD28 promoter activity to reversibly downregulate surface CD28.

    Evidence CD28 minimal-promoter reporters, in vitro transcription, EMSA and surface flow cytometry

    PMID:11544310

    Open questions at the time
    • TNF-α-responsive transcription factors at sites α/β not identified
    • Physiological contexts of CD28 downregulation not defined
  10. 2002 High

    Defined CD28-driven metabolic reprogramming, showing PI3K/Akt-dependent glycolytic upregulation that exceeds immediate energetic demand.

    Evidence CD28-KO mice, PI3K/Akt inhibitors and glucose/glycolysis/ATP-ADP assays

    PMID:12121659

    Open questions at the time
    • Did not address mitochondrial or fatty-acid metabolism
    • Link between metabolic reprogramming and effector/memory fate not established
  11. 2005 High

    Crystal and cryo-EM structures defined CD28 as a monovalent homodimer with binding and stoichiometric properties distinct from CTLA-4, constraining models of receptor triggering.

    Evidence X-ray crystallography of CD28-Fab and cryo-EM of antibody complexes

    PMID:15696168

    Open questions at the time
    • Structure of ligand-bound CD28 signaling complex not resolved here
    • Mechanistic basis of mitogenic vs non-mitogenic triggering inferred, not directly shown
  12. 2004 Medium

    Live imaging placed CD28 at the immature immunological synapse co-localized with the TCR, acting within seconds of the Ca2+ rise to stabilize the synapse.

    Evidence Live T cell-APC imaging with CD28-KO/reconstituted cells and single-cell Ca2+ recording

    PMID:15128767

    Open questions at the time
    • Single-lab imaging study
    • Molecular machinery anchoring CD28 to the immature synapse not defined
  13. 2009 Medium

    Resolved CD28 spatiotemporal signaling into TCR-CD28 microclusters that associate with PKCθ and sustain kinase-driven signaling at a synapse subregion after mature synapse formation; separately showed CD28 suppresses Th17 differentiation via IL-2/IFN-γ.

    Evidence Dynamic synapse imaging of tagged molecules; cytokine-blockade differentiation assays in human and mouse cells

    PMID:19333372 PMID:19426213

    Open questions at the time
    • Microcluster work described in review of prior imaging
    • Th17 suppression mechanism downstream of IL-2/IFN-γ not molecularly defined
  14. 2011 High

    Established B7-H2 (ICOSL) as a human-specific CD28 ligand that costimulates primary and memory T cells, broadening the CD28 ligand repertoire.

    Evidence Receptor array plus human T cell costimulation and signaling readouts (Bcl-xL, p27, phospho-ERK/AKT)

    PMID:21530327

    Open questions at the time
    • Relative physiological contribution of B7-H2 vs B7-1/B7-2 not quantified
    • Mouse-human divergence mechanism not explored
  15. 2013 High

    Conditional knockouts and epistasis defined cell-intrinsic CD28 functions: maintenance of Foxp3+ Treg fitness and identity, and ITK-dependent licensing of autoreactive T cell tissue trafficking.

    Evidence Treg-specific CD28 cKO with competitive reconstitution; Itk/Ctla4 double-KO with tissue histology and diabetogenic transfer

    PMID:23281398 PMID:24270545

    Open questions at the time
    • Treg CD28 signaling effectors maintaining CTLA-4/PD-1/CCR6 not pinpointed
    • Direct link from CD28 to ITK activation not biochemically resolved
  16. 2013 High

    Micropatterning showed costimulation requires CD3-CD28 spatial co-proximity, controlled by actin-constrained transport of active Lck, defining a physical basis for functional convergence.

    Evidence Spatially controlled ligand micropatterns, Lck phospho-imaging, actin disruption and mobility measurements in primary T cells

    PMID:24379441

    Open questions at the time
    • Reaction-diffusion model not validated in physiological APC contacts
    • Identity of CD28-proximal Lck substrates not defined
  17. 2014 High

    Showed CD28 augments CD3-associated traction forces through PI3K and links to phospho-Pyk2 complexes; separately identified CD28/PI3K/Akt/FoxO3a/Bim pro-survival signaling co-opted by multiple myeloma cells.

    Evidence Traction force microscopy with PI3K inhibitors; PI3K/Akt inhibitors, FoxO3a/Bim blots and in vivo Vk*MYC myeloma model with CD28 blockade

    PMID:24469820 PMID:24782505

    Open questions at the time
    • Mechanical signaling role in physiological T cell activation not fully defined
    • Therapeutic implications of myeloma CD28 dependence beyond mouse model unestablished
  18. 2016 Medium

    Defined disease-relevant CD28 mechanisms: superantigen direct engagement of CD28/B7-2 homodimer interfaces to force excessive costimulation, and a CTLA4-CD28 fusion that converts inhibitory signals to stimulatory ones.

    Evidence Homodimer-interface peptide binding with cytokine and lethal challenge assays; RNA-seq fusion identification and ectopic expression with phospho-AKT/ERK readouts

    PMID:26819049 PMID:27708164

    Open questions at the time
    • Superantigen mechanism mapped via peptides, not full complex structures
    • Fusion oncogenicity shown in cell lines, not primary lymphoma cells
  19. 2017 High

    Two structural/mechanistic studies defined membrane-level gating of CD28: phospholipid sequestration of signaling motifs released by TCR-induced Ca2+ as a dual positive-feedback circuit, and transient Cpt1a-driven mitochondrial priming enabling protective memory.

    Evidence NMR of CD28 TMD with lipids plus Ca2+ and mutagenesis assays; CD28-KO with miR-33 manipulation, Cpt1a perturbation, EM, metabolic flux and in vivo memory assays

    PMID:28919076 PMID:29058713

    Open questions at the time
    • Quantitative thresholds of the Ca2+/lipid switch in vivo not defined
    • Upstream regulators coupling CD28 to Cpt1a/miR-33 not fully mapped
  20. 2020 High

    Extended CD28 pro-survival signaling beyond T cells to long-lived plasma cells, defining an SLP76-dependent ROS/NF-κB/IRF4 metabolic survival program.

    Evidence CD28 activation in LLPCs vs SLPCs with metabolic, ROS, NF-κB and IRF4-knockdown survival assays

    PMID:32579940

    Open questions at the time
    • How differential SLP76 expression rewires CD28 output not mechanistically resolved
    • Relationship to T cell CD28 metabolic programs not directly compared
  21. 2021 Medium

    Showed CD28-transmembrane-domain CARs heterodimerize with endogenous CD28 via polar TMD residues, altering CAR responsiveness and reducing CD28 surface expression.

    Evidence Co-IP, TMD mutagenesis, anti-CD28-dependent proliferation and surface CD28 flow cytometry

    PMID:33833759

    Open questions at the time
    • Single-lab co-IP study
    • Functional consequences of endogenous CD28 sequestration in vivo not assessed
  22. 2023 High

    Identified a cis-B7:CD28 mechanism in which CD8+ T cells display B7 ligands engaging CD28 at synapse invaginations via PI3K/SNX9 membrane remodeling and PKCθ, promoting survival, migration and antitumor function.

    Evidence Live IS-invagination imaging, PI3K/SNX9 manipulation, cis-B7 T cell KO, PKCθ readouts and in vivo tumor models

    PMID:37160118

    Open questions at the time
    • Relative contribution of cis vs trans B7:CD28 signaling not quantified
    • Generality across T cell subsets beyond CD8+ not established
  23. 2024 Medium

    Demonstrated the CD28 costimulatory domain functions non-canonically in CAR-NK cells by recruiting LCK and ZAP70 to a CD28-CD3ζ platform that enhances antitumor cytotoxicity.

    Evidence Co-IP of LCK/ZAP70 with CD28-CD3ζ construct, in vitro cytotoxicity and xenograft models

    PMID:38900051

    Open questions at the time
    • Single-lab co-IP; direct enzymatic activation kinetics not measured
    • Whether endogenous NK signaling machinery is co-opted vs ectopically supplied unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CD28's separable signaling arms (survival vs proliferation vs metabolic priming) are wired to distinct downstream effectors, and how trans, cis, and reverse signaling modes are integrated at the synapse, remain incompletely defined.
  • No unified map linking individual cytoplasmic motifs to each functional output
  • Stoichiometry and structure of the ligand-engaged CD28 signaling complex unresolved
  • Quantitative balance of cis vs trans vs reverse signaling in physiological responses unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 3
Partners
CBLBCD80CD86ICOSLGLCP2PIK3PRKCQVAV1
Complex memberships
TCR-CD28 microclusterimmunological synapse

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 CD28 ligation by B7 induces tyrosine phosphorylation of specific substrates including phospholipase C gamma 1, and triggers both calcium-dependent and calcium-independent signaling cascades. CTLA-4, structurally related to CD28, binds B7 with approximately 20-fold higher affinity than CD28. Biochemical assays, tyrosine phosphorylation studies, binding affinity measurements Annual review of immunology Medium 8386518
1993 CD28-deficient mice have impaired T cell responses to lectins, fail to produce IL-2 upon lectin stimulation, show significantly decreased IL-2 receptor alpha expression, and have defective immunoglobulin class switching; however, cytotoxic T cells can still be induced, demonstrating that CD28 is not required for all T cell responses in vivo. CD28 knockout mouse model, T cell functional assays, immunoglobulin measurement Science High 7688139
1996 CD28 costimulation up-regulates Bcl-xL expression to enhance T cell survival during activation; this survival signal is independent of Fas expression and is mediated through ICE protease-dependent apoptosis pathways when absent. CD28 costimulation did not alter Bcl-2 or Fas expression. Wild-type vs CD28-deficient mice, CTLA4Ig treatment, western blot for Bcl-xL/Bcl-2/Fas, ICE protease inhibitors, apoptosis morphology assessment Journal of immunology High 8752911
1996 CD28 is required for germinal center formation in T-dependent immune responses; CD28-deficient mice fail to support proliferative expansion of B cells in follicles, preventing germinal center formation and somatic hypermutation. CD28 knockout mouse model, immunohistology of lymphoid tissue, B cell response analysis after antigen challenge Journal of immunology High 8648099
2000 Cbl-b suppresses TCR-mediated Vav (guanine nucleotide exchange factor for Rac1/Rho/CDC42) activation downstream of the TCR, and this suppression underlies the CD28 dependence of T cell activation. Cbl-b-null T cells do not require CD28 for IL-2 production; Cbl-b(-/-) mutation fully restores T-cell-dependent antibody responses in CD28-/- mice, without affecting ZAP-70, Lck, Ras/MAPK, PLCgamma-1, or Ca2+ mobilization. Cbl-b knockout mice crossed with CD28 knockout mice, IL-2 production assays, western blot for signaling intermediates, Vav activation assay Nature High 10646609
2001 A single point mutation in CD28 at tyrosine 170 (mouse)/173 (human) — the YMNM motif — uncouples SH2-mediated interactions (including PI3K and Grb2 recruitment) from CD28 signaling. This mutant CD28 cannot upregulate Bcl-xL, rendering T cells susceptible to radiation-induced death, but still prevents anergy and promotes proliferation, IL-2 secretion, and B cell help. Transgenic knockin mice expressing Y170F CD28 mutant, Bcl-xL western blot, T cell survival assays, proliferation/IL-2 measurements Nature immunology High 11276203
2002 CD28 costimulation, acting through PI3K and Akt, is required for T cells to increase glycolytic rate in response to activation. CD28 induces glucose uptake and glycolysis in excess of what is needed to maintain ATP/ADP ratios or macromolecular synthesis, suggesting it anticipates future energetic demands. CD28-deficient mice, PI3K/Akt inhibitors, glucose uptake assays, glycolysis measurements, ATP/ADP measurements Immunity High 12121659
2001 Mouse dendritic cells are induced by soluble CD28 to express IL-6 and IFN-gamma via B7-1 (CD80) and B7-2 (CD86) and p38 MAPK signaling — demonstrating bidirectional (reverse) signaling from CD28 through B7 molecules into dendritic cells. Soluble CD28 stimulation of mouse DCs, cytokine measurement, p38 MAPK inhibitor, B7-1/B7-2 blocking experiments, in vivo tumor challenge Nature immunology Medium 15467723
2005 Crystal structure of soluble CD28 in complex with a Fab fragment reveals that CD28 is a monovalent homodimer whose structural features redefine evolutionary relationships with CTLA-4, antigen receptors, and adhesion molecules, and account for distinct ligand-binding and stoichiometric properties compared to CTLA-4. Cryo-EM comparisons of CD28 with mitogenic vs non-mitogenic antibody complexes place new constraints on models of receptor triggering. X-ray crystallography of soluble CD28-Fab complex, cryo-electron microscopy Nature immunology High 15696168
1998 CD28 affects the earliest TCR signaling events: inhibiting CD28/B7 interaction results in impaired TCR-induced tyrosine phosphorylation of the zeta chain and ZAP-70, and strongly diminished downstream signaling including Ca2+/calcineurin, ERK/MAPK, and JNK pathways, under physiological conditions of antigen presentation. Jurkat cells and primary TCR-transgenic T cells stimulated with antigen/superantigen on B7-expressing APCs, anti-CD28 blocking, western blot for phosphorylation of TCR zeta, ZAP-70, downstream signaling European journal of immunology Medium 9692882
2000 CD28 can activate PI3K and cooperate with adapters Vav and SLP-76 to independently induce IL-2 and IL-4 transcription in the absence of TCR ligation, providing a molecular basis for in trans costimulation. Biochemical signaling assays, IL-2/IL-4 reporter assays, CD28 mutants Immunological reviews Low 12670393
2000 The YMNM motif of CD28 cytoplasmic domain, when mutated at position N191 (retaining PI3K binding), abolishes IL-2 promoter activation, whereas Y189F (disrupting PI3K binding) only reduces it, suggesting that PI3K associated with the YMNM motif acts as a negative mediator of CD28-mediated IL-2 gene transcription. CD28 point and deletion mutants expressed in Jurkat cells, IL-2 promoter reporter assays, PI3K pharmacological inhibitors, constitutively active PI3K overexpression Journal of biological chemistry Medium 11113113
2004 CD28 accumulates at the immunological synapse before c-SMAC formation (in the immature synapse), co-localizing with TCR, and exerts effects on initiation and stabilization of the synapse within seconds of TCR-mediated calcium rise, regulating downstream T cell proliferation. Live imaging of T cell–APC interactions, CD28-deficient and reconstituted murine cells, single-cell calcium recording, synapse morphology analysis Journal of immunology Medium 15128767
2009 CD28 forms TCR-CD28 microclusters in cooperation with TCRs at the immunological synapse, associates with PKCtheta, and after mature IS formation, CD28 microclusters accumulate at a specific subregion of the IS where they continuously assemble with kinases (not TCRs) to generate sustained T cell signaling. Dynamic imaging of immunological synapse, fluorescent protein-tagged molecules, microcluster analysis Immunological reviews Medium 19426213
2011 B7-H2 (ICOSL) acts as a ligand for CD28 and CTLA-4 in humans (but not mice) through distinctive binding domains from B7-1/B7-2. B7-H2-CD28 interaction costimulates human T cell primary and memory responses, inducing Bcl-xL, downregulating p27(kip1), and triggering ERK and AKT kinase-dependent signaling, similar to B7-1/B7-2. Receptor array assay, co-stimulation functional assays with human T cells, western blot for Bcl-xL, p27(kip1), phospho-ERK, phospho-AKT Immunity High 21530327
2013 CD28 has an obligate cell-intrinsic function in Foxp3+ Tregs postmaturation: Treg-specific CD28 knockout mice develop severe autoimmunity despite normal Treg numbers, with dampened CTLA-4, PD-1, and CCR6 expression and pronounced proliferative/survival disadvantage in Tregs under competitive conditions. Treg-specific conditional CD28 knockout mice (Cre-lox), autoimmunity phenotyping, flow cytometry for CTLA-4/PD-1/CCR6, competitive reconstitution experiments Journal of clinical investigation High 23281398
2014 CD28 and CD3 provide complementary functions in T cell traction force generation: force generation is associated with CD3/TCR complex engagement, while CD28 engagement increases traction forces associated with CD3 through the PI3K signaling pathway rather than through direct cell-surface coupling. Force generation is concentrated at the cell periphery and associated with molecular complexes containing phosphorylated Pyk2. Traction force microscopy using micrometer-scale elastomer pillar arrays, primary human and mouse T cells, PI3K inhibitors, Pyk2 immunofluorescence, TCR-specific T cells on peptide-loaded MHC pillars PNAS High 24469820
2013 Functional convergence of CD28 costimulation and TCR signaling requires spatial co-proximity within the immunological synapse: micrometer-scale separation of CD3 and CD28 ligands curtails T cell activation. Active Lck is concentrated to regions of CD3 engagement with low diffusion rates, suggesting costimulation is controlled by a reaction-diffusion balance of active Lck transport to CD28 vs. its deactivation. Disruption of actin cytoskeleton increases Lck mobility and rescues activation by spatially separated CD3/CD28. Micropatterned surfaces with spatially controlled ligand presentation, primary human and mouse CD4+ T cells, Lck phosphorylation imaging, actin cytoskeleton disruption, FRAP-like mobility measurements Molecular and cellular biology High 24379441
2017 CD28 transmembrane signaling is regulated by two counteractive factors: acidic phospholipids sequester CD28 signaling motifs within the membrane to limit basal signaling, while TCR-induced local Ca2+ increase directly disrupts the CD28-lipid interaction, releasing signaling motifs. TCR, Ca2+, and CD28 form a dual-positive-feedback circuit that amplifies T cell signaling and antigen sensitivity. NMR spectroscopy of CD28 transmembrane domain with lipids, Ca2+ measurement in T cells, mutagenesis of CD28 charged residues, functional T cell signaling assays Nature structural & molecular biology High 29058713
2017 CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a) before the first cell division upon T cell activation, facilitating mitochondrial fatty acid oxidation (FAO), mitochondrial elongation, and enhanced spare respiratory capacity (SRC). Without CD28, microRNA-33 (a target of TXNIP) attenuates Cpt1a expression, resulting in metabolically compromised cells. This early CD28-dependent mitochondrial priming enables T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation — features of protective memory T cells. CD28-deficient T cells, miR-33 manipulation, Cpt1a overexpression/knockdown, mitochondrial morphology imaging (electron microscopy), metabolic flux assays (oxygen consumption, FAO), in vivo memory T cell functional assays Cell High 28919076
2014 CD28 pro-survival signaling in multiple myeloma cells is dependent on downstream activation of PI3K/Akt, inactivation of transcription factor FoxO3a, and decreased expression of pro-apoptotic Bim. Blocking CD28-CD80/CD86 interaction abrogates DC-mediated protection of MM cells against chemotherapy-induced death in vitro and in vivo. PI3K/Akt inhibitors, FoxO3a/Bim western blots, CD28 crosslinking with agonistic antibodies or DCs, in vivo Vk*MYC murine myeloma model with CD28 blockade, tumor burden measurement Blood High 24782505
2016 The CTLA4-CD28 gene fusion product (extracellular CTLA4 domain fused to CD28 cytoplasmic domain) transforms inhibitory signals into stimulatory signals for T-cell activation, enhancing proliferation and AKT and ERK phosphorylation when ectopically expressed in Jurkat and H9 cells. RNA sequencing to identify fusion, RT-PCR/Sanger sequencing in 115 T-cell lymphoma samples, ectopic expression of fusion in Jurkat/H9 cells, proliferation assays, western blot for phospho-AKT and phospho-ERK Haematologica Medium 26819049
2020 CD28 transduces pro-survival signaling specifically in long-lived plasma cells (LLPCs) through differential SLP76 expression. CD28 signaling in LLPCs increases glucose uptake, mitochondrial mass/respiration, and reactive oxygen species (ROS) production. CD28-mediated mitochondrial respiration, NF-κB activation, and survival are ROS-dependent. IRF4 (a NF-κB target) is upregulated by CD28 in LLPCs and is required for CD28-mediated metabolic and survival program. CD28 activation in LLPCs vs SLPCs, SLP76 expression analysis, glucose uptake assays, mitochondrial mass/respiration measurements, ROS detection, NF-κB reporter/western blot, IRF4 knockdown, survival assays Cell reports High 32579940
2021 CARs containing a CD28 transmembrane domain (TMD) form heterodimers with endogenous CD28 in human T cells; this dimerization is dependent on polar amino acids in the CD28-TMD and is distinct from CD8-TMD-containing CARs which do not form such heterodimers. CD28-TMD heterodimers respond to anti-CD28 stimulation for CAR-dependent proliferation but do not respond to CD80/CD86 stimulation and reduce CD28 cell-surface expression. Co-immunoprecipitation, anti-CD28 stimulation-dependent proliferation assays, surface CD28 expression by flow cytometry, mutagenesis of polar residues in CD28-TMD Frontiers in immunology Medium 33833759
2023 CD8+ T cells display B7 ligands (CD80/CD86) on their surface that interact with CD28 in cis at membrane invaginations of the immunological synapse. This cis-B7:CD28 interaction is driven by PI3K and sorting-nexin-9 (SNX9)-mediated membrane remodeling. cis-B7:CD28 signaling occurs through PKCθ and promotes CD8+ T cell survival, migration, and cytokine production. Loss of T cell-intrinsic cis-B7:CD28 interactions decreases intratumoral T cells and accelerates tumor growth in mouse models. Live imaging of IS membrane invaginations, PI3K/SNX9 genetic/pharmacological manipulation, cis-B7 knockout on T cells, PKCθ signaling readouts, in vivo mouse tumor models Immunity High 37160118
2016 Bacterial superantigens hyperinduce inflammatory cytokines by directly engaging both CD28 and its coligand B7-2 (CD86) at their respective homodimer interfaces — sites remote from where B7-2 and CD28 normally interact — thereby potently enhancing the avidity of the B7-2:CD28 interaction and forcing excessive costimulatory signaling. Binding studies with CD28 and B7-2 homodimer interface peptides, cytokine production assays, murine lethal superantigen challenge with mimotope peptides PNAS Medium 27708164
2024 In CAR-NK cells, CD28 costimulatory domain linked to CD3ζ creates a signaling platform that recruits LCK and ZAP70, initiating a kinase cascade that enhances CAR-NK cell antitumor efficacy and long-term cytotoxicity; this is a non-canonical role since CD28 is not inherently present in mature NK cells. Co-immunoprecipitation of LCK/ZAP70 with CD28-CD3ζ CAR construct, in vitro cytotoxicity assays, multiple xenograft tumor models in vivo Cancer discovery Medium 38900051
2001 TNF-alpha directly inhibits CD28 gene transcription by reducing DNA-protein complex formation at two sequence motifs (site alpha and beta) of the CD28 minimal promoter, including the transcriptional initiator sequences, resulting in reversible downregulation of CD28 surface expression. Reporter gene bioassays with CD28 minimal promoter, in vitro transcription assays, EMSA (DNA-protein binding), flow cytometry for CD28 surface expression Journal of immunology Medium 11544310
2009 CD28 co-stimulation suppresses Th17 differentiation through an IL-2 and IFN-gamma-dependent mechanism; blockade of CD28/B7 interactions facilitates both murine and human Th17 cell differentiation, and this suppression is not mediated through increased Foxp3+ T cells. Anti-CD28 antibody, CTLA4-Ig blockade, cytokine measurement (IL-17, IL-2, IFN-gamma, IL-10), flow cytometry for Foxp3+ cells, DC co-culture experiments PloS one Medium 19333372
2013 CD28-activated Tec family kinase ITK specifically licenses autoreactive T cells to traffic from lymphoid organs into peripheral tissues to mount destructive immune responses; loss of ITK in CTLA-4-deficient mice does not block T cell activation/proliferation but prevents tissue infiltration and fatal autoimmunity. Itk(-/-); Ctla4(-/-) double knockout mice, T cell localization by tissue histology, T cell activation/proliferation assays, ITK pharmacological inhibitors, diabetogenic T cell transfer model Nature medicine High 24270545
2022 CARMIL2 is required for canonical NF-κB activation (but not AP-1 or NFAT) in T cells stimulated via CD28; CARMIL2-deficient patients phenocopy CD28-deficient patients in showing defective CD4+ and CD8+ memory T cells and TREG counts, but additionally show NK cell and memory B cell deficiencies, indicating CARMIL2 governs immunological pathways beyond CD28. Patient-derived cells from 89 CARMIL2-deficient patients, NF-κB/AP-1/NFAT reporter assays upon CD28 stimulation, flow cytometry for lymphocyte subsets, somatic reversion analysis Journal of experimental medicine Medium 36515678

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 CD28/B7 system of T cell costimulation. Annual review of immunology 2086 8717514
2002 The B7-CD28 superfamily. Nature reviews. Immunology 1341 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 1251 8386518
2002 The CD28 signaling pathway regulates glucose metabolism. Immunity 1195 12121659
1993 Differential T cell costimulatory requirements in CD28-deficient mice. Science (New York, N.Y.) 1050 7688139
2002 Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nature biotechnology 826 11753365
2016 CD28 Costimulation: From Mechanism to Therapy. Immunity 741 27192564
1990 Role of the CD28 receptor in T-cell activation. Immunology today 713 2162180
2009 CD28 and CTLA-4 coreceptor expression and signal transduction. Immunological reviews 687 19426212
2001 T-cell regulation by CD28 and CTLA-4. Nature reviews. Immunology 687 11905831
2009 CD28(-) T cells: their role in the age-associated decline of immune function. Trends in immunology 513 19540809
2000 Cbl-b regulates the CD28 dependence of T-cell activation. Nature 497 10646609
2011 CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease. Immunology 407 21711350
1993 CD28- T lymphocytes. Antigenic and functional properties. Journal of immunology (Baltimore, Md. : 1950) 367 8381831
1998 CD28/B7 costimulation: a review. Critical reviews in immunology 351 9784967
2011 Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family. Immunological reviews 312 21488898
1992 Identification and distribution of the costimulatory receptor CD28 in the mouse. Journal of immunology (Baltimore, Md. : 1950) 311 1320641
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 286 12876557
1997 Costimulation of CD28- T lymphocytes by 4-1BB ligand. Journal of immunology (Baltimore, Md. : 1950) 252 8992967
2017 Mitochondrial Priming by CD28. Cell 246 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 224 15467723
2001 The immunological synapse and CD28-CD80 interactions. Nature immunology 224 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 214 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 203 24469820
1996 CD28 is required for germinal center formation. Journal of immunology (Baltimore, Md. : 1950) 190 8648099
2013 An obligate cell-intrinsic function for CD28 in Tregs. The Journal of clinical investigation 185 23281398
2007 CD8+ CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. Journal of immunology (Baltimore, Md. : 1950) 184 17878327
2019 The Evolving Role of CD8+CD28- Immunosenescent T Cells in Cancer Immunology. International journal of molecular sciences 165 31181772
2005 Crystal structure of a soluble CD28-Fab complex. Nature immunology 158 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) 148 10352273
1998 CD28 expression in T cell aging and human longevity. Experimental gerontology 139 9615924
2009 The clinical utility of inhibiting CD28-mediated costimulation. Immunological reviews 138 19426230
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 126 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
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 109 12963692
2014 CD28 negative T cells: is their loss our gain? American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 108 25323029
2005 The B7/CD28 costimulatory family in autoimmunity. Immunological reviews 107 15790355
2021 The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28. Frontiers in immunology 104 33833759
2002 CD28 function: a balance of costimulatory and regulatory signals. Journal of clinical immunology 102 11958588
1998 Expression of the costimulatory receptor CD30 is regulated by both CD28 and cytokines. Journal of immunology (Baltimore, Md. : 1950) 101 9498756
2024 The B7:CD28 family and friends: Unraveling coinhibitory interactions. Immunity 99 38354702
1998 CD28 affects the earliest signaling events generated by TCR engagement. European journal of immunology 91 9692882
2009 CD28 co-stimulation down regulates Th17 development. PloS one 90 19333372
2002 Fine mapping of an IgE-controlling gene on chromosome 2q: Analysis of CTLA4 and CD28. The Journal of allergy and clinical immunology 89 12417883
2004 Critical role of OX40 in CD28 and CD154-independent rejection. Journal of immunology (Baltimore, Md. : 1950) 83 14734751
2009 Dynamic regulation of T-cell costimulation through TCR-CD28 microclusters. Immunological reviews 82 19426213
2014 CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma. Blood 80 24782505
2004 Elevated pro-inflammatory CD4+CD28- lymphocytes and stroke recurrence and death. Neurology 76 15505163
2016 Costimulation Blockade in Autoimmunity and Transplantation: The CD28 Pathway. Journal of immunology (Baltimore, Md. : 1950) 75 27591335
2015 The story of CD4+ CD28- T cells revisited: solved or still ongoing? Journal of immunology research 71 25834833
2002 CD8+CD28- T cells: certainties and uncertainties of a prevalent human T-cell subset. Immunology and cell biology 68 11869357
2018 Programmed cell death protein 1 activation preferentially inhibits CD28.CAR-T cells. Cytotherapy 67 30309710
2016 Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma. Haematologica 64 26819049
2010 Activating NK-cell receptors co-stimulate CD4(+)CD28(-) T cells in patients with rheumatoid arthritis. European journal of immunology 59 19904767
2023 cis-B7:CD28 interactions at invaginated synaptic membranes provide CD28 co-stimulation and promote CD8+ T cell function and anti-tumor immunity. Immunity 58 37160118
2011 Regulation of NF-κB induction by TCR/CD28. Immunologic research 58 21717079
1996 Regulation of T cell activation by CD28 and CTLA4. Advances in experimental medicine and biology 58 8910687
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
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 54 29058713
2003 Costimulation of human CD28- T cells by 4-1BB ligand. European journal of immunology 53 12645943
2003 Differences in CCR5 expression on peripheral blood CD4+CD28- T-cells and in granulomatous lesions between localized and generalized Wegener's granulomatosis. Clinical immunology (Orlando, Fla.) 53 12865065
2000 CD3zeta and CD28 down-modulation on CD8 T cells during viral infection. Blood 53 10910918
2024 CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis. Cancer discovery 52 38900051
2004 Proliferation and apoptosis of human CD8(+)CD28(+) and CD8(+)CD28(-) lymphocytes during aging. Experimental gerontology 51 15050288
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
2005 CD28 superagonists: mode of action and therapeutic potential. Immunology letters 45 16054703
2004 CD28 signals in the immature immunological synapse. Journal of immunology (Baltimore, Md. : 1950) 45 15128767
2002 Proliferative arrest and cell cycle regulation in CD8(+)CD28(-) versus CD8(+)CD28(+) T cells. Human immunology 45 12392852
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
1995 Potential roles of the B7 and CD28 receptor families in autoimmunity and immune evasion. Clinical immunology and immunopathology 44 7535672
2020 CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival. Cell reports 43 32579940
2000 Novel role of phosphatidylinositol 3-kinase in CD28-mediated costimulation. The Journal of biological chemistry 42 11113113
2004 EphA3 is induced by CD28 and IGF-1 and regulates cell adhesion. Experimental cell research 40 14697337
1999 Peripheral human CD8(+)CD28(+)T lymphocytes give rise to CD28(-)progeny, but IL-4 prevents loss of CD28 expression. International immunology 39 10421790
2017 Membrane Rafts in T Cell Activation: A Spotlight on CD28 Costimulation. Frontiers in immunology 38 29163534
2022 Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency. The Journal of experimental medicine 37 36515678
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
2012 CD28-specific immunomodulating antibodies: what can be learned from experimental models? American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 35 22471377
1996 Induction of autoimmunity in the absence of CD28 costimulation. Journal of immunology (Baltimore, Md. : 1950) 35 8759765
2024 CD19-CD28: an affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy. Blood 34 38437725
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
1997 The CD28-B7 costimulatory pathway and its role in autoimmune disease. Journal of leukocyte biology 33 9261329

Missed literature

Know a paper Affinage missed for CD28? Flag it for the maintainers and the community.

No submissions yet.