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CD19
Identifiers
AliasesCD19, B4, CVID3, CD19 molecule
External IDsOMIM: 107265; MGI: 88319; HomoloGene: 1341; GeneCards: CD19; OMA:CD19 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

930

12478

Ensembl

ENSG00000177455

ENSMUSG00000030724

UniProt

P15391

P25918

RefSeq (mRNA)

NM_001178098
NM_001770
NM_001385732

NM_009844
NM_001357091

RefSeq (protein)

NP_001171569
NP_001761

NP_033974
NP_001344020

Location (UCSC)Chr 16: 28.93 – 28.94 MbChr 7: 126.01 – 126.01 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

B-lymphocyte antigen CD19, also known as CD19 molecule (Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19.[5][6] In humans, CD19 is expressed in all B lineage cells.[7][8] Contrary to some early doubts, human plasma cells do express CD19.[9][10] CD19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.[8]

Structure

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In humans, CD19 is encoded by the 7.41 kilobase CD19 gene located on the short arm of chromosome 16.[11][12] It contains at least fifteen exons, four that encode extracellular domain and nine that encode cytoplasmic domains, with a total of 556 amino acids.[12] Experiments show that there are multiple mRNA transcripts; however, only two have been isolated in vivo.[11]

CD19 is a 95 kDa Type I transmembrane glycoprotein in the immunoglobulin superfamily (IgSF) with two extracellular C2-set Ig-like domains and a relatively large, 240 amino acid, cytoplasmic tail that is highly conserved among mammalian species.[11][13][14][15] The extracellular C2-type Ig-like domains are divided by a potential disulfide linked non-Ig-like domain and N-linked carbohydrate addition sites.[14][16] The cytoplasmic tail contains at least nine tyrosine residues near the C-terminus.[11][14] Within these residues, Y391, Y482, and Y513 have been shown to be essential to the biological functions of CD19.[17] Phenylalanine substitution for tyrosine at Y482 and Y513 leads to the inhibition of phosphorylation at the other tyrosines.[11][18]

Expression

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CD19 is widely expressed during all phases of B cell development until terminal differentiation into plasma cells. During B cell lymphopoiesis, CD19 surface expression starts during immunoglobulin (Ig) gene rearrangement, which coincides during B lineage commitment from hematopoietic stem cell.[8] Throughout development, the surface density of CD19 is highly regulated.[11] CD19 expression in mature B cells is threefold higher than that in immature B cells.[11] CD19 is expressed on all normal, mitogen-stimulated, and malignant B cells, excluding plasma cells[inconsistent]. CD19 expression is even maintained in B lineage cells that undergo neoplastic transformation.[7][18] Because of its ubiquity on all B cells, it can function as a B cell marker and a target for immunotherapies targeting neoplastic lymphocytes.[8][11]

Function

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Role in development & survival

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Decisions to live, proliferate, differentiate, or die are continuously being made during B cell development.[19] These decisions are tightly regulated through B cell receptor (BCR) interactions and signaling. The presence of a functional BCR is necessary during antigen-dependent differentiation and for continued survival in the peripheral immune system.[14] Essential to the functionality of a BCR is the presence of CD19.[20] Experiments using CD19 knockout mice found that CD19 is essential for B cell differentiative events including the formation of B-1, germinal center, and marginal zone (MZ) B cells.[14][21][22] Analysis of mixed bone marrow chimeras suggest that prior to an initial antigen encounter, CD19 promotes the survival of naive recirculating B cells and increases the in vivo life span of B cells in the peripheral B cell compartment.[23] Ultimately, CD19 expression is integral to the propagation of BCR-induced survival signals and the maintenance of homeostasis through tonic signaling.

BCR-independent

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Paired box transcription factor 5 (PAX5) plays a major role in B cell differentiation from pro B cell to mature B cell, the point at which the expression of non-B-lineage genes is permanently blocked.[23][24][25] Part of B cell differentiation is controlling c-MYC protein stability and steady-state levels through CD19, which acts as a PAX5 target and downstream effector of the PI3K-AKT-GSK3β axis. CD19 signaling, independent of BCR functions, increases c-MYC protein stability. Using a loss of function approach, researchers found reduced MYC levels in B cells of CD19 knockdown mice.[23] CD19 signaling involves the recruitment and activation of phosphoinositide 3-kinase (PI3K) and later downstream, the activation of protein kinase B (Akt). The Akt-GSK3β axis is necessary for MYC activation by CD19 in BCR-negative cells, with higher levels of Akt activation corresponding to higher levels of MYC.[23][26] CD19 is a crucial BCR-independent regulator of MYC-driven neoplastic growth in B cells since the CD19-MYC axis promotes cell expansion in vitro and in vivo.[23][26]

CD19/CD21 complex

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On the cell surface, CD19 is the dominant signaling component of a multimolecular complex including CD21 (CR2, a complement receptor), TAPA-1 (a tetraspanin membrane protein), and CD225.[11][23] The CD19/CD21 complex arises from C3d binding to CD21; however, CD19 does not require CD21 for signal transduction. CD81, attached to CD19, is a part of the tetraspanin web, acts as a chaperone protein, and provides docking sites for molecules in various different signal transduction pathways.[11]

BCR-dependent

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While colligated with the BCR, the CD19/CD21 complex bound to the antigen-complement complex can decrease the threshold for B cell activation. CD21, complement receptor 2, can bind fragments of C3 that have covalently attached to glycoconjugates by complement activation.[27] Recognition of an antigen by the complement system enables the CD19/CD21 complex and associated intracellular signaling molecules to crosslink to the BCR. This results in phosphorylation of the cytoplasmic tail of CD19 by BCR-associated tyrosine kinases, ensuing is the binding of additional Src-family kinases, augmentation of signaling through the BCR, and recruitment of PI3K. The localization of PI3K initiates another signaling pathway leading to Akt activation. Varying expression of CD19 on the cell surface modulates tyrosine phosphorylation and Akt kinase signaling and by extension, MHC class II mediated signaling.[11]

Activated spleen tyrosine kinase (Syk) leads to phosphorylation of the scaffold protein, BLNK, which provides multiple sites for tyrosine phosphorylation and recruits SH2-containing enzymes and adaptor proteins that can form various multiprotein signaling complexes. In this way, CD19 can modulate the threshold for B cell activation. This is important during primary immune response, prior to affinity maturation, amplifying the response of low affinity BCRs to low concentrations of antigen.[11][27]

Interactions

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CD19 has been shown to interact with:

In disease

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Autoimmunity & immunodeficiency

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Mutations in CD19 are associated with severe immunodeficiency syndromes characterized by diminished antibody production.[28][29] Additionally, mutations in CD21 and CD81 can also underlie primary immunodeficiency due to their role in the CD19/CD21 complex formation.[30] These mutations can lead to hypogammaglobulinaemia as a result of poor response to antigen and defective immunological memory.[31] Researchers found changes in the constitution of B lymphocyte population and reduced amounts of switched memory B cells with high terminal differentiation potential in patients with Down syndrome.[32] CD19 has also been implicated in autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and may be a useful treatment target.[13][16][33]

Mouse model research shows that CD19 deficiency can lead to hyporesponsiveness to transmembrane signals and weak T cell dependent humoral response, that in turn leads to an overall impaired humoral immune response.[21][22] Additionally CD19 plays a role in modulating MHC Class II expression and signaling, which can be affected by mutations. CD19 deficient B cells exhibit selective growth disadvantage; therefore, it is rare for CD19 to be absent in neoplastic B cells, as it is essential for development.[23]

Cancer

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Since CD19 is a marker of B cells, the protein has been used to diagnose cancers that arise from this type of cell - notably B cell lymphomas, acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).[8] The majority of B cell malignancies express normal to high levels of CD19. The most current experimental anti-CD19 immunotoxins in development work by exploiting the widespread presence of CD19 on B cells, with expression highly conserved in most neoplastic B cells, to direct treatment specifically towards B-cell cancers.[13][34] However, it is now emerging that the protein plays an active role in driving the growth of these cancers, most intriguingly by stabilizing the concentrations of the MYC oncoprotein. This suggests that CD19 and its downstream signaling may be a more attractive therapeutic target than initially suspected.[23][26]

CD19-targeted therapies based on T cells that express CD19-specific chimeric antigen receptors (CARs) have been utilized for their antitumor abilities in patients with CD19+ lymphoma and leukemia, first against Non-Hodgkin's Lymphoma (NHL), then against CLL in 2011, and then against ALL in 2013.[8][35][36][37] CAR-19 T cells are genetically modified T cells that express a targeting moiety on their surface that confers T cell receptor (TCR) specificity towards CD19+ cells. CD19 activates the TCR signaling cascade that leads to proliferation, cytokine production, and ultimately lysis of the target cells, which in this case are CD19+ B cells. CAR-19 T cells are more effective than anti-CD19 immunotoxins because they can proliferate and remain in the body for a longer period of time. This comes with a caveat since now CD19− immune escape facilitated by splice variants, point mutations, and lineage switching can form as a major form of therapeutic resistance for patients with ALL.[38]

References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

CD19

View on Grokipedia
from Grokipedia
CD19 is a 95 kDa transmembrane glycoprotein and a member of the immunoglobulin superfamily, serving as a critical co-receptor in B cell signaling and expressed exclusively on B lymphocytes from the pro-B cell stage through mature B cells, as well as on follicular dendritic cells. Encoded by the CD19 gene located on chromosome 16p11.2, it features an extracellular domain with two C2-type immunoglobulin-like folds, a single transmembrane helix, and a cytoplasmic tail of 242 amino acids containing nine tyrosine residues that facilitate phosphorylation and recruitment of signaling molecules such as Src-family kinases and PI3K. Discovered in the 1980s as the B4 antigen via monoclonal antibody screening, CD19 integrates with the B cell receptor (BCR) complex—including CD21, CD81, and Leu-13 (CD225)—to amplify BCR signaling, lower activation thresholds, and regulate B cell development, proliferation, differentiation, and survival. In normal physiology, CD19 modulates by fine-tuning responses to antigens, ensuring balanced production and preventing ; its deficiency, as seen in rare genetic mutations, leads to and impaired humoral responses due to disrupted BCR signaling. Aberrant CD19 expression or function contributes to malignancies, where it is expressed in nearly all cases of B-cell acute lymphoblastic leukemia (B-ALL) and most non-Hodgkin lymphomas, promoting lymphomagenesis through pathways like c-Myc activation. As a pan-B cell marker, CD19 enables precise diagnosis of neoplasms via and , distinguishing them from other hematopoietic lineages. CD19 has emerged as a prime therapeutic target in oncology, particularly for relapsed or refractory cancers, through bispecific antibodies (e.g., ), immunotoxins, and especially chimeric receptor () T-cell therapies like (approved 2017 for pediatric/young adult B-ALL, with complete remission rates exceeding 80% in some cohorts) and (approved 2017 for large ), which induce aplasia as an on-target effect. Recent advances as of 2025, including next-generation CAR designs with fast off-rate domains (e.g., obecabtagene autoleucel, approved 2024 for B-ALL), aim to mitigate due to escape and improve safety profiles, with ongoing phase 1/2 trials exploring CD19 targeting in autoimmune diseases like systemic lupus erythematosus by depleting autoreactive . Despite challenges like and , CD19-directed immunotherapies represent a in precision for disorders.

Structure and Genetics

Gene Organization

The human CD19 gene is located on the short arm of at band p11.2, specifically at genomic coordinates 28,931,965–28,939,342 (GRCh38.p14 assembly), spanning approximately 7.38 kb of genomic DNA and comprising 15 exons. The gene structure includes 14 coding exons that encode the canonical , with the first exon primarily containing the (UTR). The promoter region of the CD19 gene lies upstream of exon 1 and is regulated by -specific transcription factors, notably BSAP (Pax-5), which binds to specific sites to drive lineage-restricted expression during development. Additional regulatory elements, including enhancers responsive to early factors like EBF, contribute to transcriptional control, ensuring CD19 activation coincides with B lineage commitment. The gene exhibits evolutionary conservation across mammals, with orthologs in 96 , reflecting its essential in B signaling; sequence identity in the extracellular and cytoplasmic domains is particularly high between human and rodent counterparts. Sequence variants in CD19, such as single nucleotide polymorphisms in promoter and coding regions, have been associated with increased susceptibility to autoimmune diseases like systemic lupus erythematosus in certain populations. Germline mutations, including frameshifts and missense changes, underlie type 3 (CVID3), disrupting B function. Alternative splicing of CD19 pre-mRNA produces multiple isoforms, but the canonical transcript (ENST00000538922.8; NM_001770.6) results from inclusion of all 15 exons, yielding a 1,918 bp mRNA that translates to the predominant 556-amino acid protein isoform essential for coreceptor activity. Isoforms arising from , such as omission of exons 5–6, alter the and are less abundant.

Protein Structure

CD19 is a 95 kDa type I transmembrane composed of 556 in humans. The protein features an extracellular N-terminal domain, a single transmembrane , and a C-terminal cytoplasmic tail, classifying it within the . The extracellular region spans approximately 272 and contains two C2-set immunoglobulin-like domains, which mediate interactions with ligands such as complement receptor CD21. These domains adopt an elongated β-sandwich fold, as revealed by crystallographic studies. The transmembrane domain, comprising about 22 , anchors CD19 in the plasma membrane, while the intracellular cytoplasmic tail consists of 240 with nine conserved residues that serve as phosphorylation sites.00426-0) Post-translational modifications significantly influence CD19's structure and function, including N-linked at five key sites (Asn86, Asn125, Asn138, Asn181, and Asn265) in the extracellular domain, which contribute to the protein's mature molecular weight and stability. Structural insights from cryo-EM studies, such as the 3.8 resolution structure of the CD19-CD81 complex, depict an elongated ectodomain resting atop the partner, highlighting the immunoglobulin domains' architecture. Additionally, crystal structures indicate a potential for dimerization through C-terminal domain swapping between protomers, forming a pseudosymmetric assembly.

Expression

Cellular Distribution

CD19 is primarily expressed on B-lineage cells throughout their development, beginning at the early pro-B cell stage and persisting through mature B cells in the periphery, but it is absent on terminally differentiated plasma cells. This B-lineage restricted pattern underscores its role as a pan-B cell marker for identifying these populations via . In addition to B cells, CD19 is expressed at low levels on localized to germinal centers in secondary lymphoid tissues. The surface density of CD19, quantified by as mean fluorescence intensity, is approximately threefold higher on mature s than on immature s. CD19 expression is absent on T cells, natural killer cells, and non-hematopoietic cell types, confirming its specificity to the B lineage and select accessory cells.

Developmental Regulation

CD19 expression is tightly regulated during B cell , with upregulation occurring progressively from the pre-B cell stage to mature B cells. Transcription factors such as Pax5 and EBF1 play pivotal roles in this process by activating B cell-specific genes, including CD19. Specifically, EBF1 enables Pax5 binding to the CD19 promoter, promoting its transcription and thereby facilitating the transition to mature B cell stages. This synergistic action ensures that CD19 surface expression increases, marking commitment to the B lineage. Cytokines in the microenvironment further modulate CD19 expression during early development. Interleukin-7 (IL-7), produced by stromal cells, enhances CD19 surface levels on B cell precursors in a dose-dependent manner, with detectable increases as early as day 1 of exposure and up to a twofold elevation by days 3-4. This effect is particularly pronounced in CD34+/CD19+ pro-B cells, supporting proliferation and differentiation without similar impacts from other cytokines like IL-3 or IL-6. IL-7 signaling thus integrates environmental cues to fine-tune CD19 as a hallmark of B cell maturation in the . Epigenetic modifications provide an additional layer of control over CD19 expression. During differentiation, the CD19 locus undergoes programmed , converting (5mC) to (5hmC) via Tet2 and Tet3 enzymes, which is essential for proper gene activation and lineage-specific expression. This demethylation is enriched at enhancer-like elements associated with H3K4me1 and H3K27 marks, promoting an open state conducive to transcription at the CD19 promoter. Aberrant maintenance of methylation patterns impairs this process, underscoring the role of these modifications in developmental progression. Upon terminal differentiation into plasma cells, CD19 expression is downregulated through transcriptional repression mediated by Blimp-1 (encoded by ). Blimp-1 directly binds the Pax5 promoter, reducing Pax5 mRNA levels by up to 16-fold and thereby extinguishing Pax5-dependent activation of CD19. This leads to diminished CD19 mRNA and surface protein in plasma cells, facilitating their specialized antibody-secreting function. The Blimp-1-Pax5 axis thus enforces the loss of identity markers like CD19 during plasmacytic commitment. Recent studies from 2023 highlight of CD19 via microRNAs, with miR-150 emerging as a key modulator in B cell maturation. miR-150, highly expressed in mature s, influences differentiation by targeting factors like c-Myb and FOXP1. Dysregulation of miR-150 has been linked to altered activity. Post-translational mechanisms also contribute to CD19 surface expression during development. serves as a chaperone for the mature glycoform of CD19, ensuring proper trafficking to the cell surface, while CD21 inversely modulates CD19 levels, with CD21 deficiency leading to 19–36% increases in CD19 surface expression. Additionally, a juxtamembrane basic region in CD19 interacts with (PtdIns(4,5)P2) to regulate its activation state.

Physiological Functions

B Cell Development and Survival

CD19 plays a critical role in expansion within the and the survival of peripheral s during normal . In the , CD19 supports the proliferation and maturation of pre-B cells by modulating (BCR) signaling thresholds, ensuring efficient transition to immature B cells. Without CD19, B cell precursors develop normally through the pro-B and pre-B stages but exhibit reduced output of immature and mature B cells, leading to diminished peripheral pools. Studies in CD19 mice demonstrate this dependency, showing normal early compartments but a dramatic reduction in splenic follicular B cells (approximately 80-90% decrease) and near-complete absence of marginal zone B cells, highlighting CD19's necessity for peripheral B cell and longevity. These models also reveal impaired B-1 cell development, further underscoring CD19's contribution to overall B cell survival in secondary lymphoid organs. CD19 promotes B cell growth and resistance to apoptosis through activation of the PI3K pathway and upregulation of MYC-driven processes. Upon BCR engagement, CD19 recruits PI3K to generate PIP3, which activates downstream effectors like AKT to deliver anti-apoptotic signals, thereby enhancing B cell viability in the absence of exogenous stimuli. This PI3K-dependent mechanism is essential for tonic BCR signaling that maintains basal survival of mature B cells. Independently of BCR, CD19 drives MYC expression to support proliferative growth, as evidenced by accelerated lymphomagenesis in MYC-transgenic mice overexpressing CD19 and delayed tumor progression in CD19-deficient counterparts. In CD19 knockout models, these pathways are disrupted, resulting in heightened apoptosis and reduced B cell expansion, confirming CD19's role in integrating growth and survival cues. In , CD19 facilitates formation and responses by optimizing activation thresholds. CD19-deficient mice exhibit profoundly impaired T cell-dependent humoral responses, with fewer and smaller upon , leading to reduced class-switched production. This defect arises from CD19's enhancement of BCR and CD21/CD35 coreceptor signaling, which promotes B cell proliferation and differentiation within . Consequently, CD19 ensures robust affinity maturation and generation, critical for long-term protective immunity.

Signal Transduction Mechanisms

CD19 signal transduction primarily involves the phosphorylation of its nine conserved cytoplasmic tyrosine residues by Src-family kinases, notably Lyn and Fyn, which are activated upon B cell receptor (BCR) engagement or through basal mechanisms. Lyn, in particular, forms a constitutive complex with CD19, facilitating rapid tyrosine phosphorylation that creates docking sites for downstream effectors and amplifies signaling cascades independent of direct BCR crosslinking. This phosphorylation event is essential for CD19's role in enhancing B cell responsiveness, as demonstrated in studies of CD19-deficient models where Src kinase activity and BCR-induced phosphorylation are markedly reduced. A key aspect of CD19 signaling is the recruitment of phosphoinositide 3-kinase (PI3K) to its phosphorylated tyrosine motifs, specifically Y482 and Y513 in humans, via the p85 regulatory subunit's SH2 domains. This binding activates PI3K, leading to the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) at the plasma membrane, which in turn recruits and activates Akt (also known as protein kinase B) through pleckstrin homology domain binding. Akt activation promotes cell survival, proliferation, and metabolic processes critical for B cell function by phosphorylating targets such as FOXO transcription factors and GSK3β. This pathway accounts for a significant portion of CD19-mediated PI3K activity, with mutations at these tyrosines abolishing PI3K association and impairing downstream signaling in primary B cells. In addition to BCR-dependent amplification, CD19 supports BCR-independent tonic signaling that maintains baseline survival and without stimulation. This constitutive activity involves low-level of CD19 tyrosines and PI3K engagement, providing a survival signal analogous to tonic BCR output but distinct in its reliance on CD19's interactions, such as with PtdIns(4,5)P2. Disruption of this tonic signaling, as seen in CD19-deficient models, leads to impaired mature B cell fitness and peripheral accumulation. CD19 signaling is tightly regulated by mechanisms, including phosphatases associated with CD5 and CD72. CD5, expressed on a subset of s, recruits SHP-1 phosphatase to counteract Src kinase activity and CD19, thereby dampening excessive activation and maintaining signaling thresholds. Similarly, CD72 binds CD19 and associates with SHP-1, promoting of CD19 tyrosines and limiting PI3K to prevent hyperresponsiveness. These inhibitory interactions ensure balanced signaling, with CD72 deficiency resulting in enhanced activation and . Quantitatively, CD19 lowers the activation threshold for BCR signaling by approximately 100- to 1000-fold, enabling to respond to weaker . This amplification can be conceptually modeled as an effective signal strength equaling the basal BCR signal multiplied by a CD19 co-signal factor, where the factor reflects enhanced recruitment of effectors like PI3K (e.g., effective signal = BCR signal × CD19 amplification). Such models highlight CD19's rheostat-like function in tuning B cell sensitivity. CD19 briefly integrates with BCR pathways to further potentiate these effects during antigen encounter.

Coreceptor Complexes

CD19 integrates into a multi-subunit coreceptor complex on the surface of , consisting of CD19, CD21 (, CR2), (also known as TAPA-1 or Leu-13), and sometimes CD225, which collectively modulate B cell activation thresholds. This complex assembles through extracellular interactions, such as the binding between the large extracellular loop of and the Ig-like domains of CD19, as well as intracellular associations involving the cytoplasmic tails of CD19 and that facilitate signal propagation. The formation of this complex is essential for coordinating responses to antigens, with acting as a scaffold that stabilizes CD19 and CD21 in proximity to the (BCR). A key feature of the complex is the ability of CD21 to bind C3d-opsonized , which links complement-mediated innate immunity to adaptive responses by delivering complement-tagged immune complexes directly to the BCR via the coreceptor. This bridging enhances the efficiency of recognition, allowing low-avidity interactions to trigger robust signaling. The coreceptor complex stabilizes signaling and lowers the activation threshold for detection by up to two orders of magnitude, enabling proliferation with as few as 100 BCRs engaged per cell. Recent structural studies, including cryo-electron microscopy analyses, have revealed that CD19-CD81 assembly involves a dynamic interface where CD81's extracellular loop 2 (EC2) clamps onto CD19's membrane-proximal domain, promoting complex integrity and facilitating co-ligation with the BCR during encounter. Functional assays demonstrate that cells expressing the intact CD19/CD21/ complex exhibit enhanced intracellular calcium flux upon BCR stimulation compared to those with disrupted complex formation, such as in -deficient models, underscoring the complex's role in amplifying early signaling events. This potentiation supports broader downstream pathways, including PI3K activation, to fine-tune fate decisions.

Molecular Interactions

Binding Partners

CD19 associates with tetraspanins such as , CD9, and CD82, and with the related protein CD225 (also known as Leu-13 or IFITM1), to support membrane organization in s. These interactions were identified through co-immunoprecipitation assays showing that CD19 co-precipitates with these proteins from lysates, indicating stable associations independent of signaling activation. The binding to is particularly dynamic, with structural studies revealing that the large extracellular loop of engages the Ig-like domain of CD19, as determined by cryo-electron microscopy. This interaction influences CD19 trafficking and surface expression but can be modulated during activation. CD19 also forms a coreceptor complex with (CD21/CR2) via extracellular binding, enhancing antigen-specific signaling. The cytoplasmic tail of CD19 directly interacts with regulatory proteins, including the Vav1. Upon tyrosine phosphorylation of specific residues in the CD19 tail (e.g., Y391), the of Vav1 binds with high affinity, as evidenced by binding assays and co-immunoprecipitation from activated B cells. This direct recruitment forms part of a multiprotein complex that positions Vav1 at the membrane. CD19 also links to cytoskeletal elements through its cytoplasmic tail, which associates with actin-regulating components via intermediary proteins like Vav1. Co-immunoprecipitation studies demonstrate that phosphorylated CD19 pulls down actin-associated complexes, including those involving Cγ2 and , which indirectly tether to the network. These bindings help anchor CD19 in the membrane-cytoskeletal interface, though direct affinity constants (e.g., Kd values) for actin interactions remain unquantified in primary .

Downstream Signaling Pathways

Upon engagement by upstream binding partners such as the B cell receptor (BCR), CD19 undergoes tyrosine phosphorylation, primarily at conserved motifs in its cytoplasmic domain, which recruits and activates class IA phosphoinositide 3-kinase (PI3K). This leads to the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a key second messenger that recruits and activates protein kinase B (Akt) via phosphoinositide-dependent kinase 1 (PDK1). Activated Akt then phosphorylates downstream targets, including glycogen synthase kinase-3 (GSK-3) to promote cell survival by stabilizing anti-apoptotic proteins like MCL-1, and mechanistic target of rapamycin complex 1 (mTORC1) to enhance metabolic reprogramming, protein synthesis, and B cell growth. CD19 signaling also branches into the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, where recruited guanine nucleotide exchange factors like Vav activate Ras and Raf, culminating in ERK phosphorylation to drive B cell proliferation and differentiation. Concurrently, the nuclear factor kappa B (NF-κB) pathway is engaged through phospholipase C gamma 2 (PLCγ2)-mediated diacylglycerol (DAG) production and protein kinase C (PKC) activation, leading to IκB kinase (IKK) stimulation, NF-κB nuclear translocation, and transcription of genes involved in survival, inflammation, and cytokine production. These pathways collectively amplify proliferative and transcriptional responses in B cells. CD19 exhibits significant crosstalk with ITAM-based BCR signaling, where BCR-induced Src family kinases phosphorylate CD19 to synergistically enhance PI3K recruitment and amplify downstream outputs, such as sustained and ERK , beyond what BCR alone achieves; this integration ensures threshold-dependent responses to antigens. mechanisms tightly regulate CD19 signaling to prevent excessive ; and tensin homolog (PTEN) dephosphorylates PIP3 back to PIP2, thereby limiting PI3K-Akt-mTOR activity, while Src homology 2 domain-containing 1 (SHP-1) dephosphorylates CD19 and proximal BCR components to attenuate signaling. Recent spatiotemporal phosphoproteomics studies have mapped 1,394 dynamic phosphosites in the CD19-BCR proximity interactome within minutes of , identifying key effectors like /2, Raf isoforms, and PKC family members as critical downstream targets that orchestrate these integrated pathways.

Pathological Roles

Immunodeficiencies and Autoimmunity

Mutations in the CD19 gene lead to a rare form of primary B-cell immunodeficiency characterized by hypogammaglobulinemia and impaired antibody responses, often classified as a subtype of common variable immunodeficiency (CVID). Affected individuals exhibit recurrent bacterial infections, particularly sinopulmonary, due to defective mature B-cell activation and proliferation in response to antigens, despite normal B-cell numbers. This condition results from loss-of-function mutations that disrupt CD19's role in enhancing B-cell receptor signaling, leading to reduced immunoglobulin production and poor vaccine responses. In autoimmune diseases, dysregulated CD19 expression contributes to aberrant B-cell activation. Overexpression or elevated levels of CD19 on B cells have been observed in patients with (RA) and systemic lupus erythematosus (SLE), where CD19^hi B cells display heightened metabolic activity, T-bet expression, and pro-inflammatory functions that exacerbate production and tissue damage. In SLE, increased CD19 expression is linked to enhanced BCR signaling via BAFF-R pathways, promoting B-cell hyperactivity and survival that sustains . Similarly, in RA, CD19 signaling amplifies B-cell responses to self-antigens, fostering synovial . Genetic variations in CD19 expression levels are associated with increased risk of . Quantitative differences in CD19 surface expression, influenced by genetic polymorphisms, correlate with production in both murine models and populations, where higher CD19 levels enhance B-cell signaling thresholds and predispose to lupus-like phenotypes. Direct variants altering CD19 function underscore its role in susceptibility to diseases such as SLE and . Mouse models of CD19 hyperactivity demonstrate its contribution to lupus-like autoimmunity. Transgenic mice overexpressing CD19 exhibit augmented humoral autoimmunity when crossed with Sle1 susceptibility strains, characterized by elevated autoantibodies, B-cell expansion, and immune complex deposition, though end-organ nephritis may not fully develop without additional factors. These models highlight CD19's dose-dependent role in lowering the signaling threshold for B-cell activation, leading to spontaneous autoantibody production and systemic inflammation reminiscent of human SLE. Recent clinical data position CD19 levels as potential biomarkers in Sjögren's syndrome (SS). As of 2025, studies have shown elevated proportions of CD19^+ B cells, particularly CD226^+ CD19^+ subsets, correlate with disease activity, salivary gland infiltration, and in primary SS patients, suggesting their utility in monitoring therapeutic responses and identifying high-risk individuals. These CD19^+ populations reflect ongoing B-cell dysregulation and may guide targeted interventions like CAR-T therapies.

Oncogenic Involvement in B-Cell Cancers

CD19 is uniformly expressed across most B-cell malignancies, serving as a reliable for and a key target in neoplastic processes. In (ALL), CD19 is present at normal to high levels in approximately 80% of cases, while in (DLBCL), expression is maintained at similar densities in nearly 90% of tumors. Similarly, (CLL) and other B-cell lymphomas exhibit CD19 positivity in 88% or more of instances, with rare exceptions in subsets like where diminished expression may occur. This consistent surface presence underscores CD19's role in B-cell lineage maintenance even during . Dysregulation of CD19 through or contributes to antigen escape, particularly in cases following targeted therapies. In B-ALL, up to 20% of patients experience with CD19-negative clones, frequently driven by splice variants that alter the protein's extracellular domain, preventing recognition by therapeutic agents. Point in CD19 exons, such as frameshift or deletion events, further enable immune evasion in 10-30% of large B-cell lymphomas, leading to conformational changes that abolish surface expression while preserving intracellular signaling. These alterations highlight CD19's adaptability in promoting tumor persistence under selective pressure. Hyperactive CD19 signaling drives lymphomagenesis primarily through amplification of the PI3K pathway, fostering uncontrolled B-cell proliferation and survival. In DLBCL and models, CD19 enhances PI3K recruitment, leading to sustained AKT activation that overrides apoptotic checkpoints and promotes tumor fitness. This tonic signaling, independent of stimulation, is essential for lymphoma cell viability, as disruption of CD19-PI3K interactions impairs growth in preclinical studies. In CLL, aberrant CD19-mediated PI3K hyperactivation correlates with disease progression, integrating with BCR signals to sustain malignant expansion. High CD19 expression levels serve as a prognostic indicator in CLL, with elevated densities or counts of CD19-positive lymphocytes at diagnosis associating with increased risk of progression and poorer outcomes, particularly in early-stage patients. This correlation reflects intensified signaling capacity that exacerbates disease aggressiveness.

Therapeutic Targeting

CAR-T Cell Therapies

Chimeric antigen receptor (CAR) T-cell therapies targeting CD19 represent a transformative approach in treating relapsed or refractory (R/R) B-cell malignancies, leveraging engineered T cells to recognize and eliminate CD19-expressing cancer cells. These therapies involve autologous T cells transduced with a lentiviral vector encoding a CAR construct that binds the CD19 antigen, leading to T-cell activation, proliferation, and cytotoxicity against malignant B cells. CD19's uniform expression across B-cell neoplasms, including acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphomas, makes it an ideal target, with clinical success hinging on the antigen's accessibility on the cell surface. The U.S. (FDA) has approved several CD19-directed CAR-T products. (Kymriah), approved in 2017, is indicated for pediatric and young adult patients with R/R B-cell precursor ALL and for adults with R/R large B-cell lymphoma after two or more lines of . (Yescarta), also approved in 2017, targets adults with R/R large after two or more prior lines of therapy, with expanded approval in 2022 for second-line treatment in patients ineligible for . (Tecartus), approved in 2020 for R/R and in 2021 for adult R/R B-cell precursor ALL. Lisocabtagene maraleucel (Breyanzi), approved in 2021, is indicated for adults with R/R large after two or more lines of , including , high-grade , primary mediastinal large , and grade 3B, with expanded approval in 2022 for second-line treatment after first-line therapy in patients with high-risk disease or ineligible for . These therapies predominantly utilize second-generation CAR constructs, incorporating the CD3ζ signaling domain for primary activation alongside a costimulatory domain—either CD28 for rapid effector function and cytokine production or 4-1BB for enhanced persistence and memory-like T-cell differentiation—to amplify antitumor activity upon CD19 engagement. CD28-based CARs, as in , promote swift proliferation and high peak expansion, while 4-1BB-based designs, seen in and , support longer-term remission through improved T-cell survival and reduced exhaustion. Clinical efficacy is notable, particularly in pediatric R/R B-ALL, where achieved complete remission (CR) rates of 81% in the pivotal trial, with 59% of responders maintaining remission at 12 months. In adults with R/R large , yielded objective response rates of 83%, including 58% CR, with durable responses in approximately 40% at 5 years. Real-world from 2024-2025 registries indicate 50% durable remissions beyond 12 months across indications, though outcomes vary by prior therapy lines and , with higher rates in adults compared to . Despite efficacy, challenges include (CRS), occurring in 70-90% of patients and graded severe (≥3) in 15-25%, manifesting as fever, , and managed with and supportive care. Immune effector cell-associated neurotoxicity syndrome (ICANS) affects 20-60%, with symptoms ranging from headache to seizures and , often correlating with CRS severity. Relapses due to CD19 antigen loss occur in 15-30% of cases, particularly in ALL, driven by lineage switch or mutations, limiting long-term cures. Recent advances address manufacturing and relapse issues. Allogeneic "off-the-shelf" CD19 CAR-T products, using gene-edited donor T cells to mitigate , entered phase 1/2 trials in 2024, showing preliminary CR rates of 60-70% in R/R B-cell malignancies with reduced production time. Dual-targeting constructs combining CD19 and antigens in bispecific CARs have demonstrated improved durability, with phase 1 trials reporting 80-90% CR rates and relapse rates under 10% in pediatric R/R ALL.

Monoclonal and Bispecific Antibodies

Monoclonal antibodies targeting CD19, such as , represent a key class of therapeutics for B-cell malignancies by leveraging enhanced (ADCC) and . is a humanized, Fc-engineered anti-CD19 that binds to CD19 on malignant B cells, inducing their lysis through immune effector mechanisms. It received accelerated approval from the U.S. (FDA) in July 2020 for use in combination with in adult patients with relapsed or refractory (DLBCL) ineligible for autologous transplant, based on the phase II L-MIND trial demonstrating an overall response rate of 57.5%. Bispecific antibodies, particularly T-cell engagers, have advanced CD19-targeted therapy by redirecting cytotoxic T cells to CD19-expressing tumor cells, offering an off-the-shelf alternative to cell-based approaches. , a CD19/CD3 bispecific T-cell engager, was the first such agent approved by the FDA in December 2014 for the treatment of relapsed or refractory Philadelphia chromosome-negative B-cell precursor (ALL) in adults and children, following phase II trial data showing a complete remission rate of 43% in adults. This mechanism involves simultaneous binding to CD19 on B cells and CD3 on T cells, forming an that triggers T-cell activation and serial tumor cell killing. As of 2025, remains the only FDA-approved CD19-directed bispecific antibody, though others targeting CD19 in combination with CD3 or additional antigens are in late-stage development for broader hematologic indications. Emerging bispecific constructs, such as those targeting both and , aim to achieve more comprehensive B-cell depletion by engaging dual on malignant and normal B cells, potentially reducing antigen escape. Preclinical studies in 2025 demonstrated that a CD19/CD20 bispecific with dual Fc domains enhances effector functions, including ADCC and , while achieving durable depletion of memory B cells in non-human primates. These agents are under investigation for B-cell lymphomas, where dual targeting could broaden efficacy beyond single- approaches. In autoimmune diseases, CD19-targeted antibodies are being explored to reset aberrant B-cell responses, with early clinical data supporting their use in systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). A 2024 case report highlighted the successful application of blinatumomab in a patient with refractory SSc, achieving clinical remission through targeted B-cell elimination without severe adverse events. Similarly, phase I/II trials of anti-CD19 monoclonal antibodies in SLE patients with coexisting neuromyelitis optica spectrum disorder reported sustained B-cell depletion and disease stabilization as of 2025, suggesting potential for broader autoimmune applications. Safety profiles of CD19-targeted antibodies generally show lower incidence of (CRS) compared to adoptive cell therapies, with most events being grade 1-2 and manageable via supportive care. For instance, blinatumomab-associated CRS occurred in about 15% of ALL patients in pivotal trials, resolving without long-term sequelae. Resistance mechanisms, including —where CD19 is transferred from target cells to effector cells, leading to antigen loss—have been observed in preclinical models of antibody and bispecific therapies, potentially contributing to in up to 20% of cases. These agents may synergize with CAR-T therapies in sequential regimens to overcome partial responses.

References

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC3520838/
  2. https://pubmed.ncbi.nlm.nih.gov/8528044/
  3. https://www.ema.europa.eu/en/medicines/human/EPAR/aucatzyl
  4. https://clinicaltrials.gov/study/NCT06585514
  5. https://pubmed.ncbi.nlm.nih.gov/39832905/
  6. https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177455
  7. https://rloopbase.nju.edu.cn/browser/cgi-bin/hgGene?hgsid=17310003_sathsm6duSNhtOEms03mye93BvCh&hgg_section_domains_close=0
  8. https://pmc.ncbi.nlm.nih.gov/articles/PMC364460/
  9. https://www.sciencedirect.com/science/article/abs/pii/S0161589099000929
  10. https://pubmed.ncbi.nlm.nih.gov/1714482/
  11. https://pubmed.ncbi.nlm.nih.gov/12215898/
  12. https://www.omim.org/entry/107265
  13. https://pmc.ncbi.nlm.nih.gov/articles/PMC4670800/
  14. https://www.uniprot.org/uniprotkb/P15391/entry
  15. https://ehoonline.biomedcentral.com/articles/10.1186/2162-3619-1-36
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC10839018/
  17. https://www.nature.com/articles/s41598-021-81000-5
  18. https://pubmed.ncbi.nlm.nih.gov/7686930/
  19. https://www.pnas.org/doi/10.1073/pnas.1604365113
  20. https://pmc.ncbi.nlm.nih.gov/articles/PMC133916/
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC10172652/
  22. https://doi.org/10.1016/j.jbior.2025.101116
  23. https://pubmed.ncbi.nlm.nih.gov/14634103/
  24. https://pmc.ncbi.nlm.nih.gov/articles/PMC2747094/
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC2787092/
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC3777394/
  27. https://pubmed.ncbi.nlm.nih.gov/22546857/
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC3426298/
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC2346595/
  30. https://pubmed.ncbi.nlm.nih.gov/28931676/
  31. https://pubmed.ncbi.nlm.nih.gov/10358152/
  32. https://pubmed.ncbi.nlm.nih.gov/10933394/
  33. https://www.cell.com/immunity/pdf/S1074-7613(02)00426-0.pdf
  34. https://pubmed.ncbi.nlm.nih.gov/11042164/
  35. https://www.embopress.org/doi/10.15252/embj.201797980
  36. https://www.nejm.org/doi/full/10.1056/NEJMoa051568
  37. https://pubmed.ncbi.nlm.nih.gov/11751967/
  38. https://academic.oup.com/intimm/article/17/7/869/675095
  39. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2013.00457/full
  40. https://www.science.org/doi/10.1126/science.abd9836
  41. https://www.sciencedirect.com/science/article/pii/S1074761300804185
  42. https://www.jbc.org/article/S0021-9258%2819%2959269-9/fulltext
  43. https://elifesciences.org/articles/52337
  44. https://www.jci.org/articles/view/39748
  45. https://pubmed.ncbi.nlm.nih.gov/11239449/
  46. https://www.cell.com/immunity/pdf/S1074-7613%2802%2900483-1.pdf
  47. https://pubmed.ncbi.nlm.nih.gov/1373518/
  48. https://pmc.ncbi.nlm.nih.gov/articles/PMC2743935/
  49. https://pubmed.ncbi.nlm.nih.gov/9857038/
  50. https://pubmed.ncbi.nlm.nih.gov/1702139/
  51. https://doi.org/10.1016/S1074-7613(00)80568-3
  52. https://pubmed.ncbi.nlm.nih.gov/15187135/
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC3412259/
  54. https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00660-0
  55. https://academic.oup.com/rheumatology/article/63/Supplement_1/keae163.218/7656283
  56. https://karger.com/kdd/article/8/6/437/824573/Aberrant-B-Cell-Activation-in-Systemic-Lupus
  57. https://pubmed.ncbi.nlm.nih.gov/11086109/
  58. https://pubmed.ncbi.nlm.nih.gov/17763445/
  59. https://acrjournals.onlinelibrary.wiley.com/doi/abs/10.1002/art.22825
  60. https://pubmed.ncbi.nlm.nih.gov/40787453/
  61. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1468469/full
  62. https://pmc.ncbi.nlm.nih.gov/articles/PMC9796473/
  63. https://www.sciencedirect.com/science/article/abs/pii/S215226502502840X
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC6863137/
  65. https://aacrjournals.org/clincancerres/article/30/14/2895/746332/Sequencing-of-Anti-CD19-Therapies-in-the
  66. https://aacrjournals.org/cancerres/article/74/16/4318/592933/B-cell-Expansion-and-Lymphomagenesis-Induced-by
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC5983214/
  68. https://www.nature.com/articles/s41467-021-23752-2
  69. https://link.springer.com/article/10.1007/s10654-005-3777-6
  70. https://www.jci.org/articles/view/80010
  71. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome
  72. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-adults-relapsed-or-refractory-large-b-cell-lymphoma
  73. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axicabtagene-ciloleucel-large-b-cell-lymphoma
  74. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axicabtagene-ciloleucel-second-line-treatment-large-b-cell-lymphoma
  75. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus
  76. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi
  77. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-large-b-cell-lymphoma
  78. https://pmc.ncbi.nlm.nih.gov/articles/PMC6410718/
  79. https://ashpublications.org/bloodadvances/article/9/11/2763/536292/Real-world-outcomes-for-young-adult-patients
  80. https://ashpublications.org/blood/article/130/21/2295/36661/Kinetics-and-biomarkers-of-severe-cytokine-release
  81. https://pmc.ncbi.nlm.nih.gov/articles/PMC7295115/
  82. https://www.nature.com/articles/s41591-021-01436-0
  83. https://www.antibodysociety.org/approvals/fda-grants-first-approval-to-tafasitamab-cxix/
  84. https://www.amgen.com/newsroom/press-releases/2014/12/fda-approves-blincyto-blinatumomab-immunotherapy-for-the-treatment-of-relapsed-or-refractory-bcell-precursor-acute-lymphoblastic-leukemia
  85. https://rupress.org/jem/article/221/5/e20240499/276688/CD19-directed-T-cell-engaging-antibodies-for-the
  86. https://www.nature.com/articles/s41598-025-16461-z
  87. https://www.ejcancer.com/article/S0959-8049%2824%2900727-5/fulltext
  88. https://www.jrheum.org/content/52/Suppl_1/266.3
  89. https://pubmed.ncbi.nlm.nih.gov/26374073/
  90. https://pmc.ncbi.nlm.nih.gov/articles/PMC9136177/
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