CTLA-4

CTLA4 is the acronym for Cytotoxic T-Lymphocyte Antigen 4 and is classified as CD152. CTLA-4, like PD-1 (Programmed Death 1), is a member of the extended CD28 / CTLA4 family and in humans is encoded by the CTLA4 gene on chromosome 2.

CTLA-4 is expressed on the surface of activated CD4+ T helper cells, cytotoxic T cells, and also regulatory T cells. CTLA4 is a cytokine that plays an important role in tumor cell evasion.

CTLA4 belongs to the family of anti-inflammatory immune checkpoints (ICs). Anti-inflammatory immune checkpoints inhibit the immune reactivity of T lymphocytes, in contrast to proinflammatory ICs, which increase the immune reactivity of T lymphocytes. Immune checkpoints are activated by matching cytokines (ligands) presented and released by other cells.

CTLA4 inhibits the proliferation of T cells by decreasing the expression of the IL-2 receptor, thus also decreasing IL-2 production. Furthermore, it arrests the cell cycle. In this way, CTLA4 is able to raise the activation threshold of T cells. Thus, activation of T cells is impeded or prevented.

CTLA4 has an extracellular V-shaped domain and a transmembrane domain. In terms of its structure, the protein has great similarities to the costimulatory CD28, whereby both protein receptors also bind to CD80 and CD86.

Heterozygous germline mutations in the CTLA4 gene leads to "CTLA4 insufficiency". This is characterized by a complex immune dysregulation syndrome. Clinical studies of CTLA4 mutation carriers showed reduced penetrance and variable expressivity, suggesting modifying factors (Mitsuiki N et al.2019). To date, > 140 CTLA4 mutation carriers have been reported. Patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphoid infiltration to multiple organs . In these patients, the CTLA4 expression level in Treg cells was reduced, whereas the number of Treg cells was increased.

An autosomal-dominantly inherited mutation in the CTLA4 gene leads to a rare, clinically highly variable immune dysregulation syndrome (symptom complex of antibody deficiency, recurrent respiratory infections, and enteropathies with diarrhea). Apparently, the amount of CTLA4 molecules present in/on T cells is significant for immune homeostasis.

Furthermore, CTLA4 plays an important role in tumor diseases. Monoclonal antibodies against CTLA-4 and anti-PD-1 such as ipilimumab and tremelimumab have demonstrated survival benefits in numerous tumor types, including melanoma and non-small cell lung cancer (Durgeau A et al.2018; Manieri NA et al.2017). Ipilumumab is a fully humanized T-cell activator that specifically blocks the inhibitory signaling of the antigen CTLA-4 (CD152 see CD classification). Suppression of CTLA4 signaling enhances the T cell response.

Ipilimumab is used both monotherapeutically (malignant melanoma / prostate carcinoma) and now also combinatorially together with nivolumab in advanced malignant melanoma.

However, the immunostimulatory mechanism predisposes patients to immune-related side effects, of which gastrointestinal effects such as diarrhea and colitis are the most common (Gupta A et al.2015).

The biologic "Abatacept", a fusion protein of the Fc part of human IgG1 and the extracellular domain of human CTLA4, is used in the therapy of rheumatoid arthritis. Through the CTLA4 domain, Abatacept can bind to CD80 and CD86 of antigen-presenting cells (APCs) and thus prevent costimulation of the T cell by an antigen-presenting cell.

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