CTLA4

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.

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.