CD3G

Official Full Name

CD3 gamma subunit of T-cell receptor complex

Organism

Homo sapiens

GeneID

917

Background

The protein encoded by this gene is the CD3-gamma polypeptide, which together with CD3-epsilon, -delta and -zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T-cell receptor-CD3 complex. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. The genes encoding the epsilon, gamma and delta polypeptides are located in the same cluster on chromosome 11. Defects in this gene are associated with T cell immunodeficiency. [provided by RefSeq, Jul 2008]

Synonyms

T3G; IMD17; CD3GAMMA; CD3-GAMMA;

Protein Sequence

MEQGKGLAVLILAIILLQGTLAQSIKGNHLVKVYDYQEDGSVLLTCDAEAKNITWFKDGKMIGFLTEDKKKWNLGSNAKDPRGMYQCKGSQNKSKPLQVYYRMCQNCIELNAATISGFLFAEIVSIFVLAVGVYFIAGQDGVRQSRASDKQTLLPNDQLYQPLKDREDDQYSHLQGNQLRRN

Open

Disease

Breast cancer, Colorectal cancer, Malignant digestive organ neoplasm, Prostate cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

5 +

Discontinued Drug

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Detailed Information

The CD3G gene, located at 11q23.3, encodes the CD3γ polypeptide, an essential component of the T cell receptor (TCR)–CD3 complex and a member of the immunoglobulin superfamily. It is clustered with CD3D and CD3E, suggesting coordinated regulation and evolutionary conservation. The gene contains multiple exons and promoter motifs for transcription factors such as NFAT and AP-1, key regulators of T cell development and activation.

The CD3γ protein is a 182–amino acid, ~21 kDa type I transmembrane protein consisting of an extracellular immunoglobulin-like domain, a transmembrane region, and a short cytoplasmic tail that harbors an ITAM (immunoreceptor tyrosine-based activation motif). CD3γ pairs with CD3ε to form a heterodimer that stabilizes the TCR complex. Its cytoplasmic ITAM is rapidly phosphorylated upon antigen recognition, triggering downstream signaling, while its dileucine motif regulates receptor internalization and recycling. CD3γ is expressed from early thymocyte stages and maintained in mature T cells, reflecting its specialized role in T cell biology.

Figure 1. Schematic overview of the TCR complex and its downstream signaling pathways, with red circles indicating phosphate groups. (Kent A, et al., 2021)

Biological Function and Immunological Role

CD3γ is indispensable for coupling antigen recognition to intracellular signaling. Following TCR engagement with peptide–MHC, its ITAM is phosphorylated by Src kinases (Lck, Fyn), recruiting ZAP-70 and activating pathways such as Ca²⁺ flux, PKC, and Ras–MAPK, leading to T cell activation, cytokine secretion, and proliferation.

Beyond signal initiation, CD3γ controls TCR internalization and turnover through its dileucine motif, fine-tuning receptor density and signaling thresholds. CD3G deficiency alters thymocyte selection and can prolong positive selection, highlighting its role in signal intensity regulation. CD3γ also contributes to immune synapse stability and may regulate TCR degradation and renewal, particularly under chronic antigen exposure.

Clinical Relevance and Therapeutic Potential

CD3G mutations cause primary immunodeficiencies, ranging from severe combined immunodeficiency (SCID) to milder phenotypes with autoimmunity. Patients present with recurrent infections, autoimmunity (e.g., ITP, hemolytic anemia), and growth retardation. Laboratory findings include reduced or dysfunctional T cells with impaired TCR-mediated responses. Diagnosis requires genetic sequencing; treatment options range from supportive care to hematopoietic stem cell transplantation, while gene therapy remains experimental.

Beyond congenital defects, CD3γ alterations are linked to autoimmunity and T cell malignancies, though causality remains unclear. In immunotherapy, CD3 has been a classical target—OKT3 (muromonab-CD3) and modern bispecific antibodies like blinatumomab primarily engage CD3ε, but CD3γ represents a potential alternative target with distinct activation and safety profiles.

Therapeutic challenges include cytokine release syndrome, neurotoxicity, and on-target/off-tumor toxicity. Targeting CD3γ specifically could modulate activation strength and persistence, potentially improving CAR-T cell design and reducing T cell exhaustion. With advances in protein engineering and gene editing, CD3γ may emerge as a novel immunotherapy target for immunodeficiencies, autoimmunity, and cancer.

Reference

Crawford A, Chiu D. Targeting Solid Tumors Using CD3 Bispecific Antibodies. Mol Cancer Ther. 2021 Aug;20(8):1350-1358.
Saber H, Del Valle P, Ricks TK, et al. An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection. Regul Toxicol Pharmacol. 2017 Nov;90:144-152.
Kent A, Longino NV, Christians A, et al. Naturally Occurring Genetic Alterations in Proximal TCR Signaling and Implications for Cancer Immunotherapy. Front Immunol. 2021 May 3;12:658611.

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