CTLA-4 (CD152) is a member of the immunoglobulin super family and is in the T-cell cytoplasm, and is expressed in CD4 + and CD8+ T cells and regulatory T cells.
The initial stage of activation of the immune response occurs mainly in the lymph nodes, as the first signal comprises T-cell receptor recognition of specific antigens presented by major histocompatibility complexes on antigen presenting cell (APC).
It is a protein receptor that like PD-L1, works to down regulate the immune system’s natural response to attack tumor cells and generally expressed on Tregs.
The second is a costimulatory receptor activation involving the finding of CD28 on T-cell surface with its CD80 and CD86 ligands on the APC, a required steps T-cell activation and expansion.
CTLA-4 is a co-inhibitory T-cell receptor that competes with CD28 for binding with its APC ligands, which can inhibit T-cell activation.
CTLA-4 is expressed on regulatory T-cells involved in suppressing the activity of cytotoxic T-cells.
CTLA-4 inhibits AKT phosphorylation by using protein phosphatase 2A to mediate the suppression of T cell activation.
There is some suggestion that CTLA-4 may deplete T regulatory cells in the tumor microenvironment.
Anti- CTLA antibodies are thought to inhibit the negative regulatory molecule CTLA-4, which functions at the activation stage of T cell priming.
A negative regulator of the immune system with a key role in endogenous and vaccine induced antitumor immunity.
CTLA-4 plays in important role in preventing auto immunity by preventing excessive T cell activation.
After T cell activation, within 48 to 72 hours the CTLA-4 migrates to the surface of the T cell.
With the exception of T regulatory cells CD4+, CD25+, Foxp3+, resting lymphocytes do not express CTLA-4 on their surface.
Expression of CTLA-4 is upgraded after binding of the T cell receptor.
Up regulation of CT LA-4 on the surface of cytotoxic T cells inhibits proliferation of these cells.
CTLA-4 has a higher affinity for B7 than for CD28 and binds to it preferentially: binding of CTLA-4 to B7 results in an inhibitory signal to the T cell and down regulates the immune response.
CTLs bind to B7-1 and B-7-2 (CD80 and CD86) ligand pair which are expressed on the surface of antigen presenting cells (APCs).
Interaction between CTLA-4 and B7-1/B7-2 activates a cell signaling cascade that results in cell cycle arrest of CTLs leading to T cell anergy and interferes with IL-2 secretion and IL-2 receptor expression.
The above process leads to inhibition of T cell priming, immune escape and tumor growth.
The binding of CD28 on CTLs to B7-1 AND B7-2 can stimulate Tcell proliferation and production of IL-2.
Impairment of the expression of CTLA-4 can result in an autoimmune disease.
Polymorphisms and mutations in the CT LA-4 gene have been associated with insulin dependent diabetes, Graves’ disease, Hashimoto’s thyroiditis, systemic lupus erythematosis, and celiac disease.
Has a key role as a negative regulator in immune activity.
A molecule that down regulates pathways of T cell activation.
Ipilimubab, a fully human monoclonal anti-body that blocks CTLA-4
A close homologue of CD28.
CTLA-4 activate inhibitory signals that converts an activated T cell into an inhibited one, to limit self damage.
Principle role is to induce peripheral immune tolerance in antigen specific T cells by induction of apotosis or functional paralysis, anergy.
Cytotoxic T lymphocytes are key to the antitumor specific response in melanomas, and various melanoma specific clones of such cells have been identified.
Ipilimumab is an CTLA-4 antobody that causes blockade of CTLA-4, resulting in prolonged T cell activation, proliferation and antitumor response.