Gene Number: 1493

Location: 2q33.2

Key Functions: Immune checkpoint regulation, T-cell activation control, immune tolerance, autoimmunity prevention

CTLA4 encodes cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a pivotal immune checkpoint receptor that plays a central role in maintaining immune equilibrium by restraining T-cell activation. Expressed on activated T lymphocytes and constitutively on regulatory T cells (Tregs), CTLA-4 functions as a critical inhibitory molecule that ensures immune responses remain proportionate and self-tolerance is preserved.

At the molecular level, CTLA-4 counterbalances the stimulatory activity of CD28, another T-cell surface receptor that binds to B7 ligands (CD80 and CD86) on antigen-presenting cells (APCs). While CD28 engagement promotes T-cell activation and proliferation, CTLA-4 binds these same ligands with significantly higher affinity, effectively sequestering them and dampening co-stimulatory signaling. This competitive inhibition results in decreased activation of downstream signaling cascades such as PI3K–Akt and NFAT, reduced production of interleukin-2 (IL-2), and overall suppression of T-cell proliferation and effector function.

CTLA-4 modulates immune responses through several interrelated mechanisms:

1. Suppression of effector T-cell activity:Upon engagement with its ligands, CTLA-4 transduces inhibitory signals that limit T-cell receptor (TCR) signaling strength, curbing excessive cytokine release and proliferation. This ensures that immune activation remains tightly regulated, preventing immunopathological damage.

   
   

2. Regulation via Tregs:In regulatory T cells, CTLA-4 serves as a major effector molecule that enforces immune suppression. Through trans-endocytosis, Tregs internalize CD80/CD86 from APC surfaces, reducing their availability to activate conventional T cells and thus maintaining peripheral immune tolerance.

   
   

3. Checkpoint integration in immune balance:By fine-tuning the threshold for T-cell activation, CTLA-4 establishes a dynamic equilibrium between immune responsiveness and restraint—essential for preventing autoimmunity while permitting effective defense against pathogens and tumors.

   
   

Genetic variations in CTLA4 can disrupt this delicate regulatory network. The most extensively studied variant, +49A>G (rs231775), results in a threonine-to-alanine substitution that alters CTLA-4 protein trafficking and expression on the cell surface. This variant diminishes inhibitory signaling capacity, leading to hyperactive T-cell responses and a heightened risk of autoimmunity. Such polymorphisms have been consistently associated with several immune-mediated diseases, including:

• Type 1 diabetes mellitus (T1D)

• Rheumatoid arthritis (RA)

• Systemic lupus erythematosus (SLE)

• Autoimmune thyroid disorders (Graves’ disease, Hashimoto’s thyroiditis)

• Celiac disease

• Multiple sclerosis (MS)

  
  

Beyond its role in autoimmunity, CTLA-4 has profound implications in cancer immunotherapy. Tumor cells often exploit CTLA-4–mediated inhibition to evade immune detection. Pharmacological blockade of CTLA-4 using immune checkpoint inhibitors (notably ipilimumab) restores T-cell activity, enabling more effective antitumor immune responses. However, therapeutic inhibition of CTLA-4 can lead to immune-related adverse events, underscoring its indispensable role in maintaining immune self-regulation.

In summary, CTLA4 serves as a molecular sentinel that enforces immune self-tolerance and prevents uncontrolled T-cell activation. Its fine-tuned inhibitory function underpins the balance between immune vigilance and restraint, making it a cornerstone of both autoimmune disease susceptibility and immunotherapeutic innovation.