CTLA-4/CD28 Signaling Pathway

1. CTLA-4/CD28 Signaling Pathway Antigen-specific activation of naive CD4+ T cell is one of the important events in the initiation of adaptive immunity. Therefore, the event is controlled by a finely tuned balance of stimulatory and inhibitory regulatory signals. There have two distinct signals to regulate adaptive immunity. The first signal of this two-signal model is antigen-specific and is produced by interaction of the TCR with antigenic peptide presented in context with MHC antigens. The second signal is referred to the T cell surface molecule CD28. CD28 delivers a costimulatory signal upon interaction with B7 molecules present on APC. Activation of the TCR in the presence of costimulatory signals leads to T cell clonal expansion and initiation of effector functions. Due to the need to maintain a balance between immune activation and tolerance, there is also a protein molecule, molecule-4(CTLA-4), that antagonizes CD28. CTLA-4 is a cell surface molecule that is closely related to CD28, and it shows a potent negative regulator of T cell activation. cytotoxic T lymphocyte-associated CD28 signaling In addition to TCR engagement by peptide, ligation of co-stimulatory molecules is also required for a productive immune response to occur. CD28 is the best characterized and most effective co-stimulatory molecule expressed by naive and primed T cells. CD28 is a 44-kDa glycoprotein that binds to B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells (APCs) CD28 might be associate, in its unphosphorylated state, with the serine/threonine protein phosphatase 2A (PP2A). On T-cell stimulation, CD28 undergoes phosphorylation on its intracellular tyrosine residues (Y), presumably leading to dissociation from PP2A and recruitment of phosphatidylinositol 3-kinase (PI3K) and (growth factor-receptor-bound protein 2 (GRB2). Activation of PI3K, which induces phosphorylation of phosphatidylinositol (PI) into phosphatidylinositol 3-phosphate (PIP3), might promote activation of protein kinase B (PKB/Akt), followed by that of nuclear factor-κB (NF-κB), resulting in BCL-XL upregulation that favours T-cell survival. Akt activation might stimulate interleukin-2 (IL-2) production. PI3K is negatively regulated by phosphatase and tensin homologue (PTEN). The carboxy-terminal proline (P) -rich region might promote IL-2 production and proliferation, perhaps by recruiting and activating Lck. https://www.creative-diagnostics.com/ctla-4-cd28-signaling-pathway.htm