CTLA-4 / CD152, the first immune checkpoint receptor to be clinically targeted, is expressed exclusively on T cells where it primarily regulates the amplitude of the early stages of T cell activation. Although the exact mechanisms of CTLA-4 / CD152 action are under considerable debate, it has been proposed that its expression on the surface of T cells dampens the activation of T cells by outcompeting CD28 in binding CD80 / B7-1 and CD86 / B7-2. CD28 signalling strongly amplifies TCR signalling to activate T cells. CD28 and CTLA-4 / CD152 share identical ligands: CD80 / B7-1 and CD86 / B7-2. Besides, a number of studies suggest that activation of the protein phosphatases, SHP2 (also known as PTPN11) and PP2A, are important in counteracting kinase signals that are induced by TCR and CD28.
Even though CTLA-4 / CD152 is expressed by activated CD8+ effector T cells, the major physiological role of CTLA-4 & CD80 (CD86) Immune Checkpoint Pathway seems to be through distinct effects on the two major subsets of CD4+ T cells: downmodulation of helper T cell activity and enhancement of regulatory T (TReg) cell immunosuppressive activity. CTLA-4 / CD152 blockade results in a broad enhancement of immune responses that are dependent on helper T cells and, conversely, CTLA-4 / CD152 engagement on TReg cells enhances their suppressive function. CTLA-4 / CD152 is a target gene of the forkhead transcription factor FOXP3, the expression of which determines the TReg cell lineage, and TReg cells therefore express CTLA-4 / CD152 constitutively. Although the mechanism by which CTLA-4 / CD152 enhances the immunosuppressive function of TReg cells is not known, TReg cell-specific CTLA-4 / CD152 knockout or blockade significantly inhibits their ability to regulate both autoimmunity and antitumour immunity. Thus, in considering the mechanism of action for CTLA-4 / CD152 blockade, both enhancement of effector CD4+ T cell activity and inhibition of TReg cell-dependent immunosuppression are probably important factors.
CTLA-4 & CD80 (CD86) Immune Checkpoint Pathway: Relatives