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T-cell surface glycoprotein CD3 zeta chain
T-cell surface glycoprotein CD3 zeta chain
T-cell surface glycoprotein CD3 zeta chain
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from Wikipedia
CD247
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCD247, CD3-ZETA, CD3H, CD3Q, CD3Z, IMD25, T3Z, TCRZ, CD247 molecule, CD3zeta
External IDsOMIM: 186780; MGI: 88334; HomoloGene: 12818; GeneCards: CD247; OMA:CD247 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

919

12503

Ensembl

ENSG00000198821

ENSMUSG00000005763

UniProt

P20963

Q3UU54
P24161

RefSeq (mRNA)

NM_000734
NM_198053
NM_001378515
NM_001378516

NM_001113391
NM_001113392
NM_001113393
NM_001113394
NM_031162

RefSeq (protein)

NP_000725
NP_932170
NP_001365444
NP_001365445

Location (UCSC)Chr 1: 167.43 – 167.52 MbChr 1: 165.62 – 165.7 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

T-cell surface glycoprotein CD3 zeta chain also known as T-cell receptor T3 zeta chain or CD247 (Cluster of Differentiation 247) is a protein that in humans is encoded by the CD247 gene.[5]

Some older literature mention a similar protein called "CD3 eta" in mice. It is now understood to be an isoform differing in the last exon.[6]

Genomics

[edit]

The gene is located on the long arm of chromosome 1 at location 1q22-q25 on the Crick (negative) strand. The encoded protein is 164 amino acids long with a predicted weight of 18.696 kiloDaltons.

Function

[edit]

T-cell receptor zeta (ζ), together with T-cell receptor alpha/beta and gamma/delta heterodimers and CD3-gamma, -delta, and -epsilon, forms the T-cell receptor-CD3 complex. The zeta chain plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. Low expression of the antigen results in impaired immune response. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[7]

Interactions

[edit]

CD247 has been shown to interact with Janus kinase 3[8] and Protein unc-119 homolog.[9]

See also

[edit]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

T-cell surface glycoprotein CD3 zeta chain

View on Grokipedia
from Grokipedia
The T-cell surface glycoprotein CD3 zeta chain, also known as CD247 or TCR zeta, is a transmembrane protein encoded by the CD247 gene on human chromosome 1q24.2 that forms a homodimer (ζζ) and serves as an indispensable subunit of the T-cell receptor (TCR)–CD3 complex, coupling antigen recognition to intracellular signal transduction pathways in T lymphocytes. This complex, comprising the antigen-specific TCR αβ (or γδ) heterodimer along with CD3 γ, δ, ε, and ζ chains in a stoichiometric ratio of 1:1:1:1:1, is expressed primarily on the surface of mature T cells and natural killer (NK) cells, where it orchestrates T-cell development, activation, proliferation, and differentiation upon engagement with peptide-major histocompatibility complex (pMHC) ligands. Structurally, the CD3 zeta chain features a short extracellular domain, a single transmembrane helix, and a long cytoplasmic tail of approximately 113 amino acids containing three immunoreceptor tyrosine-based activation motifs (ITAMs), which distinguish it from the other CD3 subunits (each with one ITAM) by providing the majority (six of ten total) of the complex's signaling motifs. Upon TCR ligation, Src family kinases such as Lck phosphorylate the ITAM tyrosines in the zeta chain, enabling recruitment and activation of the tyrosine kinase ZAP-70, which in turn initiates downstream cascades including phospholipase Cγ1 (PLCγ1) activation, calcium mobilization, and NFAT/ERK/AP-1/NF-κB transcription factor pathways critical for cytokine production and effector functions. The zeta chain is uniquely essential for TCR assembly and transport to the plasma membrane, as its absence prevents complex maturation in the endoplasmic reticulum; accordingly, biallelic mutations in CD247 cause a form of severe combined immunodeficiency (SCID) characterized by profound T-cell defects, while polymorphisms are associated with autoimmune disorders such as rheumatoid arthritis and systemic sclerosis. Additionally, the CD3 zeta chain serves as the core signaling domain in chimeric antigen receptor (CAR) T-cell therapies, enabling engineered T cells to target and eliminate cancer cells. Beyond adaptive immunity, CD3 zeta influences innate responses in NK cells via analogous signaling and has emerging roles in non-immune contexts, such as modulating neuronal excitability through interactions with EphA4 and NMDA receptors.

Discovery and Nomenclature

Historical Background

The discovery of the (TCR) complex in the early 1980s marked a pivotal advancement in understanding T-cell recognition, with the identification of CD3 components as integral to this process. In 1980, researchers observed that monoclonal antibodies targeting CD3 could block -specific human T-cell proliferation in response to soluble antigens and alloantigens, highlighting CD3's role in T-cell activation. By 1982, further studies linked CD3 to the T-cell surface structures involved in recognition, establishing it as a key component of the TCR complex. In 1983, the αβ TCR heterodimer was defined as the primary receptor, consistently associated with CD3 chains, which facilitated . The molecular characterization of the CD3 zeta chain advanced rapidly in the late through cDNA efforts. In , Weissman and colleagues cloned the murine CD3 zeta chain cDNA, revealing a predicted featuring a short extracellular domain, a transmembrane region, and a long cytoplasmic tail essential for signaling. That same year, the same group cloned and sequenced the human CD3 zeta chain (now known as CD247), confirming high to the murine version and distinguishing it from other CD3 subunits like gamma, delta, and . These studies provided the foundational genetic blueprint for the zeta chain's role within the multimeric TCR-CD3 complex. Early functional insights into the CD3 zeta chain emerged in the 1990s through genetic disruption models, particularly in knockout mice, which demonstrated its critical involvement in T-cell development and signaling. Studies using CD3 zeta-deficient mice revealed impaired T-cell maturation, with a profound reduction in surface TCR expression and accumulation of immature thymocytes. A landmark 1993 publication detailed how disruption of the CD3 zeta gene led to a structurally abnormal thymus, predominantly containing CD4⁻ CD8⁻ cells with very low TCR/CD3 levels, underscoring the zeta chain's necessity for proper thymic selection and T-cell signaling. These findings solidified the zeta chain's indispensable function in adaptive immunity, paving the way for subsequent research on T-cell receptor signaling pathways.

Gene and Protein Naming

The official gene symbol for the gene encoding the T-cell surface glycoprotein CD3 zeta chain is CD247, as designated and approved by the (HGNC ID: HGNC:1677). This symbol reflects its role in the (TCR) signaling machinery and adheres to standardized gene naming conventions established by the HGNC to ensure consistency across and databases. The corresponding protein is formally named T-cell surface glycoprotein CD3 zeta chain, with common synonyms including TCR zeta chain and T3 zeta, the latter evoking its early identification within the T3 complex. Additional aliases for both the gene and protein encompass CD3Z, CD3-ZETA, CD3H, CD3Q, TCRZ, T3Z, and IMD25, where IMD25 links it to a form of combined immunodeficiency due to mutations affecting T-cell signaling. These aliases arose from independent cloning efforts and functional studies in the 1980s, highlighting the protein's conserved role across species. The CD3 zeta chain is classified as a type I transmembrane , characterized by an N-terminal extracellular domain, a single spanning transmembrane helix, and a long C-terminal cytoplasmic tail rich in immunoreceptor tyrosine-based activation motifs (ITAMs). It functions as a critical signaling component within the TCR-CD3 complex, integrating with members (such as CD3 epsilon, gamma, and delta chains) to propagate antigen-induced signals, though the zeta chain itself lacks Ig-like domains. Historically, the nomenclature evolved from "T3 zeta" in pioneering biochemical analyses of the TCR complex during the mid-1980s, which distinguished it from other CD3 polypeptides, to the contemporary CD247 designation formalized in the (CD) system by the Human Leukocyte Differentiation Antigens workshops. This shift, culminating in the 1990s, aligned the term with data—such as the 1988 identification of the human zeta cDNA—and broader genomic standardization efforts.

Genomics

Gene Location and Organization

The CD247 gene, which encodes the T-cell surface glycoprotein CD3 zeta chain, is located on the long arm of human chromosome 1 at the q24.2 cytogenetic band, spanning approximately 88 kb from genomic position 167,430,640 to 167,518,529 on the reverse strand (GRCh38 assembly). In the mouse, the orthologous Cd247 gene resides on , covering about 88.6 kb from position 165,616,250 to 165,704,846 on the forward strand (GRCm39 assembly). This positioning places CD247 within a region associated with immune-related loci, though its precise genomic neighborhood does not overlap directly with other CD3 chain genes, which are clustered on chromosome 11q23. The gene is organized into 8 s in its canonical transcript (ENST00000362089), with the first exon containing the majority of the and the coding sequence distributed across the exons to produce a 164-amino-acid polypeptide. The overall genomic span includes a large first of approximately 78 kb, followed by smaller introns, reflecting a compact coding structure within a relatively extended locus that facilitates regulated transcription. The promoter region of CD247 features regulatory elements, including T-cell-specific enhancers that promote its expression predominantly in lymphoid tissues such as and . High-throughput sequencing data from the project have identified spatially conserved motifs within the gene, such as transcription factor binding sites and a element, which contribute to lineage-specific control in T lymphocytes. CD247 exhibits high sequence conservation across mammalian species, with approximately 81% amino acid sequence identity between and orthologs, and orthologs detected in 147 ranging from to . Evolutionarily, the gene traces its origins to the emergence of jawed vertebrates, coinciding with the development of the and the T-cell receptor-CD3 signaling complex.

Isoforms and Regulation

The CD247 gene undergoes to produce multiple isoforms of the CD3 zeta chain protein. The canonical isoform consists of 164 , including an extracellular domain, a transmembrane region, and a cytoplasmic tail with three immunoreceptor tyrosine-based motifs (ITAMs) essential for . A shorter variant results from that excludes a segment of the cytoplasmic tail, thereby reducing the number of ITAMs and potentially modulating downstream signaling. Recent studies as of 2024 have identified additional splice variants, such as CD3ι and CD3θ in murine models, which differ in the C-terminal region and influence T-cell development and , with implications for CD247 regulation. Expression of CD247 is predominantly confined to T-lymphocytes and natural killer (NK) cells, where it forms homodimers or heterodimers with the eta isoform within the T-cell receptor (TCR) complex. During T-cell activation, CD247 levels are upregulated following initial TCR engagement and downmodulation, supporting sustained immune responses; this process is regulated by transcription factors such as NFAT and NF-κB, which bind promoter elements to enhance transcription in response to antigenic stimulation. Post-transcriptional regulation further fine-tunes CD247 levels, with microRNAs like miR-181a directly targeting its mRNA to suppress expression during immune responses, thereby adjusting T-cell sensitivity to antigens. Tissue-specific patterns show high CD247 expression in immune organs such as the and , reflecting its role in T-cell development and maturation, while it is low or undetectable in non-immune tissues like liver or . These regulatory mechanisms ensure precise control of CD247 availability, with isoform variations briefly impacting TCR signaling efficiency by altering ITAM availability.

Structure

Primary Sequence and Domains

The T-cell surface glycoprotein CD3 zeta chain is a 164-amino-acid polypeptide with a predicted molecular weight of 18.7 kDa. Its primary structure includes a brief signal peptide (residues 1–21), followed by a short extracellular domain (residues 22–30, 9 amino acids), a transmembrane helix (residues 31–51, 21 amino acids), and an extended cytoplasmic tail (residues 52–164, 113 amino acids). This architecture positions the bulk of the protein intracellularly, enabling its role in signal propagation while minimizing extracellular exposure. The cytoplasmic domain harbors three immunoreceptor tyrosine-based activation motifs (ITAMs), which are critical signaling elements consisting of paired residues embedded in the YxxL/I (where x represents any and the second tyrosine follows 6–8 residues downstream). These motifs are tandemly arranged at residues 72–83 (first ITAM, containing tyrosines Y72 and Y83), 99–110 (second ITAM, Y99 and Y110), and 126–137 (third ITAM, Y126 and Y137), providing multiple docking sites for downstream effectors upon . Post-translational modifications enhance the protein's functionality and stability. The extracellular stub undergoes N-linked , which contributes to proper folding and complex assembly despite its brevity. Within the ITAMs, the residues serve as sites, primarily targeted by Src family kinases such as Lck, enabling recruitment of SH2 domain-containing proteins like ZAP70. Zeta chains associate as a disulfide-linked ζζ homodimer, facilitated by charged residue interactions (e.g., at position 34) within their transmembrane helices, which stabilizes incorporation into the TCR-CD3 complex.

Tertiary Assembly and Complex Integration

The tertiary structure of the T-cell surface glycoprotein CD3 zeta chain (CD3ζ) features a short extracellular domain, a single alpha-helical transmembrane (TM) segment, and a cytoplasmic containing three immunoreceptor tyrosine-based activation motifs (ITAMs). The extracellular domain, comprising nine , is largely unstructured and buried within the assembled (TCR)-CD3 complex, shielding it from solvent exposure and contributing to overall complex stability. The TM domain forms an that spans the , while the cytoplasmic ITAMs exist in a compact, membrane-associated conformation in the resting state but adopt an extended, accessible structure upon tyrosine phosphorylation, facilitating downstream signaling interactions. CD3ζ assembles as a disulfide-linked homodimer (ζζ) primarily through interactions in the TM region, which is stabilized by the environment. (NMR) spectroscopy has revealed the ζζ TM dimer as a left-handed coiled-coil structure, characterized by parallel alpha helices with extensive polar contacts, including hydrogen bonding between the conserved residues at position 34 in each chain of the human that are essential for dimer stability. This dimerization is further reinforced by hydrophobic interactions with , such as those in micelles mimicking cellular bilayers, ensuring the ζζ module's integrity within the plasma . In the context of the larger TCR-CD3 complex, the ζζ homodimer integrates as a key signaling subunit in an octameric assembly that includes the antigen-recognizing TCR αβ (or γδ) heterodimer, the CD3γε heterodimer, and the CD3δε heterodimer. This integration occurs via coordinate TM interactions, where the basic residue in the TCR α chain pairs with acidic residues in the CD3 TM domains to form a structured bundle, positioning the ζζ dimer to contribute six ITAMs (three per chain) out of the complex's total of ten, thereby amplifying potential. Cryo-electron (cryo-EM) structures of the complete γδ TCR-CD3 complex confirm this octameric organization, with the ζζ TM helices oriented parallel to the plane and in close proximity to the other CD3 subunits. Antigen binding to the TCR induces in the CD3ζ component, including separation of the ζζ dimer from the and exposure of its cytoplasmic ITAMs. These conformational changes, observed through NMR and simulations, involve dissociation of the ITAM tails from the inner leaflet of the plasma , transitioning from a sequestered to an extended state that promotes by Src family kinases. This lipid-dependent release mechanism ensures rapid signal initiation while preventing basal activation in unstimulated T cells.

Function

Role in T-Cell Receptor Complex

The T-cell surface glycoprotein CD3 zeta chain (CD3ζ) serves as a critical structural component of the (TCR)-CD3 complex, essential for its proper assembly and intracellular trafficking to the cell surface. Forming a disulfide-linked homodimer, CD3ζ associates non-covalently with the TCR αβ heterodimer and the CD3 γε and δε subunits via hydrophobic interactions in the , stabilizing the octameric complex and preventing its degradation. This association is indispensable for the complex's progression through the secretory pathway; in the absence of CD3ζ, incomplete complexes are retained intracellularly in the and targeted for proteasomal degradation, resulting in negligible surface expression. During T-cell development in the thymus, the CD3ζ chain plays a pivotal role in thymocyte differentiation and selection processes. Knockout mouse models lacking CD3ζ exhibit profoundly impaired thymopoiesis, with progression to double-positive (CD4⁺CD8⁺) thymocytes expressing only trace levels of surface TCR/CD3, leading to reduced numbers and compromised both positive and negative selection, underscoring CD3ζ's necessity for generating a functional T-cell repertoire. In the context of the adaptive immune response, CD3ζ enables -specific T-cell activation by bridging TCR recognition to downstream intracellular events, thereby coordinating immune effector functions. As a major constituent of the TCR-CD3 complex, CD3ζ ensures adequate complex for efficient surface presentation. Reduced CD3ζ levels, as observed in certain genetic or engineered models, diminish overall TCR density on mature T cells, thereby impairing responsiveness and immune surveillance efficacy.

Signal Transduction Mechanisms

Upon ligation of the (TCR) complex, Src family kinases, primarily Lck, initiate by phosphorylating the residues within the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 zeta chain. This phosphorylation event is triggered by conformational changes in the TCR-CD3 complex, bringing Lck into proximity with the zeta chain's cytoplasmic ITAMs, each consisting of a YxxL/I sequence flanked by acidic residues. The zeta chain contains three such ITAMs, providing multiple sites for phosphorylation that collectively amplify the initial signal; the ζ chain's three ITAMs contribute six of the ten ITAMs in the complex, enabling robust signal amplification. The phosphorylated ITAMs on the zeta chain serve as docking sites for the SH2 domains of zeta-chain-associated protein kinase 70 (ZAP-70), recruiting it to the plasma membrane. Lck subsequently phosphorylates ZAP-70 on activation loop tyrosines (e.g., Y493), enabling its autophosphorylation and full activation. Activated ZAP-70 then phosphorylates downstream adaptor proteins, such as linker for activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76), forming a signalosome that propagates pathways including phospholipase Cγ1 activation, calcium mobilization, and MAPK/ERK signaling. The presence of three ITAMs in the zeta chain enhances signal strength by offering redundant docking platforms for ZAP-70 molecules, allowing for greater recruitment and efficiency compared to chains with fewer ITAMs, such as CD3ε or δ. This multiplicity contributes to graded T-cell responses proportional to affinity, with high-affinity ligands promoting near-complete of all six zeta ITAM tyrosines. Signal termination occurs through dephosphorylation of zeta ITAMs by protein tyrosine phosphatases, notably CD45, which directly targets phosphorylated tyrosines to dampen ZAP-70 recruitment and prevent prolonged activation. CD45 also regulates Lck activity by dephosphorylating its inhibitory C-terminal tyrosine (Y505), balancing positive and negative effects on the pathway. Additionally, of the zeta chain produces isoforms (e.g., ζ-ζ, ζ-η, η-η), which modulate signaling intensity; the η isoform lacks certain ITAM tyrosines, leading to reduced phosphorylation and attenuated downstream responses like calcium flux and IL-2 production.

Interactions

Direct Binding Partners

The CD3 zeta chain (CD247), existing primarily as a disulfide-linked homodimer (ζζ), forms essential non-covalent associations with other components of the (TCR)-CD3 complex through its . Specifically, the ζζ homodimer binds to the TCRαβ heterodimer via ionic interactions involving basic residues in the TCRα transmembrane region and acidic residues in the zeta transmembrane segments, while also coordinating with the CD3γε and CD3δε heterodimers through complementary charged transmembrane interfaces that stabilize the overall octameric assembly. These interactions occur sequentially during assembly, with the ζζ dimer joining last after the formation of the TCRαβ-CD3γε-CD3δε partial complex. In terms of , each complete TCR-CD3 complex incorporates one ζζ homodimer that interacts with one TCRαβ heterodimer and two CD3 heterodimers (CD3γε and CD3δε), ensuring monovalent recognition and efficient surface expression. This defined 1:1:1:1 ratio of TCRαβ:CD3γε:CD3δε:ζζ has been confirmed through sequential with radiolabeling and analyses of endoplasmic reticulum intermediates. For signaling, the cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs) of the zeta chain serve as direct docking sites for the SH2 domains of zeta-chain-associated 70 (ZAP-70) following . This association is phosphorylation-dependent, with ZAP-70 binding specifically to dual-phosphorylated ITAM tyrosines on zeta, as demonstrated by co-immunoprecipitation and binding assays using recombinant zeta tails. Additionally, Lck (lymphocyte-specific ) interacts within the TCR-CD3 complex to initiate phosphorylation of zeta ITAMs, although its primary recruitment occurs via the CD3ε basic residue-rich , facilitating proximity-based modification of zeta. Beyond the core complex, the zeta chain's cytoplasmic domain directly binds Protein unc-119 homolog (UNC119), a chaperone involved in trafficking myristoylated proteins like Lck to the plasma membrane. This interaction, mapped to the zeta tail, has been verified through GST pull-down assays showing UNC119 association with CD3 subunits including zeta. The zeta chain also directly associates with Janus kinase 3 (JAK3) independently of receptors, via the JH4 domain of JAK3 binding to the zeta cytoplasmic tail, as evidenced by co-precipitation from T-cell lysates and in vitro GST-zeta binding experiments enabling TCR-mediated JAK3 activation.

Regulatory Modifiers

The activity of the T-cell surface glycoprotein CD3 zeta chain is modulated by several phosphatases that counteract phosphorylation of its immunoreceptor tyrosine-based activation motifs (ITAMs), thereby dampening TCR signaling. CD45, a tyrosine , specifically dephosphorylates the phosphorylated ITAMs on the CD3 zeta chain with high affinity, facilitating the termination of T-cell responses and preventing excessive activation. Similarly, the cytosolic SHP-1 (PTPN6) inhibits CD3 zeta-mediated signaling by recruiting to the activated TCR complex upon , where it dephosphorylates key substrates to attenuate proximal signaling cascades. Adaptor proteins such as SLP-76 and LAT exert indirect regulatory influence on CD3 zeta chain function by orchestrating downstream signaling complexes initiated by zeta ITAM phosphorylation. SLP-76, a cytosolic adaptor, integrates with LAT to form a signalosome that amplifies zeta-triggered pathways, including PLCγ1 activation and cytoskeletal remodeling, while fine-tuning signal duration through interactions with Vav and Nck. LAT, a transmembrane adaptor, is phosphorylated following CD3 zeta activation and recruits SLP-76 via GADS, thereby propagating and modulating the zeta-initiated signals without directly binding the zeta chain. Ubiquitin ligases like Cbl-b provide post-translational regulation by mediating K33-linked polyubiquitination of the CD3 zeta chain, thereby limiting TCR signaling potency and enforcing T-cell tolerance. The cytoplasmic domain of the CD3 zeta chain features a basic residue stretch that serves as a phosphoinositide-binding motif, anchoring the TCR/CD3 complex to rafts in the plasma membrane for enhanced signal amplification. This motif binds such as PI(4,5)P₂ and PI(3,4,5)P₃, facilitating zeta chain localization to microdomains where signaling efficiency is boosted through compartmentalized interactions, independent of ITAM . Cytoskeletal proteins, including ezrin from the ERM family, act as allosteric regulators by modulating the mobility and synaptic positioning of the CD3 zeta-containing TCR complex following activation. Ezrin links the TCR/CD3 complex to the actin cytoskeleton, tuning at the to optimize signal integration and T-cell activation threshold.

Clinical Significance

Genetic Mutations and Immunodeficiencies

Mutations in the CD247 gene, encoding the T-cell surface glycoprotein CD3 zeta chain, are associated with 25 (IMD25; OMIM #610163), an autosomal recessive (SCID)-like syndrome characterized by profound T-cell dysfunction. Homozygous mutations in CD247 disrupt the assembly and surface expression of the T-cell receptor (TCR)-CD3 complex, leading to impaired T-cell development and signaling. Common pathogenic variants include nonsense and missense mutations that result in absent, truncated, or dysfunctional CD3 zeta protein. For instance, the homozygous p.Q70X introduces a premature , preventing expression of the immunoreceptor tyrosine-based activation motifs (ITAMs) essential for , while other variants like p.Q101X and p.Y152X exhibit dominant-negative effects in heterozygous carriers by interfering with TCR assembly. Recent reports (as of 2025) describe additional cases, including heterozygous mutations (e.g., p.Q101X, p.Y152X) with dominant-negative effects and somatic reversions improving outcomes in some patients. Homozygous null mutations consistently reduce peripheral T-cell numbers, with circulating CD3+ T cells detectable but markedly decreased and hypofunctional, showing impaired proliferation in response to mitogens and antigens. Clinically, affected individuals present with recurrent bacterial, viral, and fungal infections starting in infancy, often accompanied by erythroderma, , and due to the lack of functional regulatory T cells. IMD25 is extremely rare, with fewer than 10 cases reported worldwide as of 2025, reflecting its status as a minor subtype among the genetic causes of SCID. Diagnosis typically involves demonstrating reduced surface CD3 expression on T cells and confirmatory genetic sequencing to identify biallelic CD247 variants. Therapeutic potential includes , which has restored immune function in reported cases; additionally, lentiviral vector-mediated gene correction in patient-derived cells has been shown to restore TCR surface expression and partial signaling competence in preclinical models.

Disease Associations and Therapies

Dysregulation of the CD247 gene, encoding the CD3 zeta chain, has been implicated in various autoimmune disorders beyond primary immunodeficiencies. Single nucleotide polymorphisms (SNPs) in CD247 are associated with increased susceptibility to (SLE), with studies identifying variants such as rs12141731 that confer risk across multiethnic populations by altering T-cell signaling efficiency. For instance, the rs858543 polymorphism has been linked to reduced CD247 expression, contributing to impaired immune regulation in SLE patients. Additionally, deficient CD247 expression is a hallmark of thymomas associated with Good's , a condition characterized by and , where loss of zeta chain function leads to expanded regulatory T cells and disrupted thymic output. In non-autoimmune contexts, reduced CD247 expression in peripheral T cells serves as a prognostic marker for (IPF), correlating with disease severity and poorer lung function outcomes, as lower levels reflect T-cell exhaustion and fibrosis progression. Polymorphisms in CD247, such as rs12141731, have also been associated with heightened risk of in Chinese Han populations, potentially through dysregulated T-cell responses exacerbating cardiac inflammation. Similarly, interactions between CD247 variants and environmental factors, including early-life viral exposures, modify the risk of celiac disease by influencing T-cell reactivity to antigens. In , downregulation of CD247 in facilitates immune evasion by impairing T-cell activation and , as observed in where low expression correlates with advanced differentiation and metastasis. This reduced zeta chain signaling limits T-cell surveillance, allowing tumor progression, and has been noted in as a predictor of poor due to diminished immune infiltration. Conversely, in chronic infections like , CD247 expression is typically downregulated, reflecting T-cell anergy rather than upregulation. Therapeutically, the CD3 zeta signaling domain is integral to chimeric receptor () T-cell designs, where its immunoreceptor tyrosine-based activation motifs provide potent activation signals, enhancing antitumor efficacy in second- and third-generation -T therapies for hematologic malignancies. Monoclonal antibodies targeting CD3, such as , have been employed in to modulate T-cell responses, achieving transient depletion and regulatory shifts beneficial in and early autoimmune trials, though remains a challenge. Emerging approaches incorporating CD247 supplementation have shown promise in preclinical models for SCID.

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