CD40 Protein

T-cell surface glycoprotein CD3 delta chain, also known as CD3D, is a single-pass type I membrane protein. CD3 delta/CD3d is part of the T-cell receptor/CD3 complex (TCR/CD3 complex) and is involved in T-cell development and signal transduction. The encoded membrane protein represents the delta subunit of the CD3 complex, and along with four other CD3 subunits, binds either TCR alpha/beta or TCR gamma/delta to form the TCR/CD3 complex on the surface of T cells. CD3 delta/CD3d contains an 84 amino acid extracellular domain, a 21 amino acid transmembrane domain, and a 45 amino acid cytoplasmic domain. Deleterious mutation of the CD3 delta encoding gene in the human leads to a severe combined immunodeficiency characterised by the complete absence of mature T cell subpopulations including TCR alpha/beta and TCR gamma/delta. In humans the absence of CD3 delta results in a complete arrest in thymocyte development at the stage of double negative to double positive transition and the development of gamma delta T-cell receptor-positive T cells is also impaired. CD3D, together with CD3 epsilon (CD3E), CD3 gamma and CD3 zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T cell receptor-CD3 complex. T cell receptor-CD3 complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways.CD40 is also known as TNFRSF5, Bp50, CDW40, MGC9013, TNFRSF5 and p50, is a member of the TNF receptor superfamily which are single transmembrane-spanning glycoproteins, and plays an essential role in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects. CD40 contains 4 cysteine-rich repeats in the extracellular domain, and is expressed in B cells, dendritic cells, macrophages, endothelial cells, and several tumor cell lines. Interaction of CD40 with its ligand, CD40L, leads to aggregation of CD40 molecules, which in turn interact with cytoplasmic components to initiate signaling pathways. Early studies on the CD40-CD40L system revealed its role in humoral immunity. Both CD40 and CD40 L have a membrane form and a soluble form generated by proteolytic cleavage or alternative splicing. CD40 and CD40L are widely expressed in various types of cells, among which B cells and myeloid cells constitutively express high levels of CD40, and T cells and platelets express high levels of CD40L upon activation. CD40L self-assembles into functional trimers which induces CD40 trimerization and downstream signaling. CD40/CD40L immune checkpoint leads to activation of both innate and adaptive immune cells via two-way signaling. CD40/CD40L interaction also participates in regulating thrombosis, tissue inflammation, hematopoiesis and tumor cell fate. The mechanisms of benefits include immune cell activation and tumor cell lysis/apoptosis in malignancies, or immune cell inactivation in autoimmune diseases and allograft rejection.