CTLA4, Cytotoxic T-lymphocyte protein 4, Cytotoxic T-lymphocyte-associated antigen 4, CD152
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a pivotal immune checkpoint receptor that belongs to the immunoglobulin superfamily and is homologous to the T cell co-stimulatory protein CD28. Upon T cell activation, T cells express CTLA-4 that functions as negative regulator of T cell activation in secondary lymphoid organs in order to prevent excessive immune responses and maintain immune homeostasis. As CD28, CTLA-4 interacts with the B7 proteins, CD80 and CD86, co-stimulatory molecules expressed on antigen-presenting cells (APCs). However, CTLA-4 has a 10 to 20-fold higher affinity for B7 proteins than CD28 and is thus a competitive inhibitor of B7-CD28 interactions. Since the cytoplasmic tail of CTLA-4 contains a motif that connects it to clathrin, binding of CTLA-4 to B7 proteins results in receptor-mediated endocytosis. Thereby, CTLA-4 outcompetes CD28 and reduces the amount of B7 available on APCs to provide co-stimulation via CD28. This results in the suppression of T cell activation, proliferation, and cytokine production. Noteworthy, regulatory T cells constitutively express high levels of CTLA-4 to maintain peripheral tolerance by preventing activation of self-reactive T cells. Mutations in the CTLA-4 gene are associated with several autoimmune diseases, such as diabetes type I and Graves’ disease, due to failure of peripheral tolerance. In cancer therapy, immune checkpoint inhibitors are used to block CTLA-4, which leads to increased anti-tumor immune responses. Despite the success of CTLA-4-targeted immunotherapies in cancer treatment, their use is associated with severe autoimmune and inflammatory disorders due to systemic immune activation. Ongoing research aims to refine the understanding of CTLA-4’s intricate regulatory mechanisms and develop more selective and precise immunotherapeutic approaches.
