The Roles Of 4-1BB/4-1BBL Bi-directional Signalling In Immunoregulation And Their Associated Mechanisms

Efficient activation and differentiation of T cells requires two signals: a primary signal initiated by the engagement of a TCR with a MHC/peptide complex and a secondary signal mediated through costimulatory molecules expressed on the surface of the T cell. It is currently believed that signals are usually transduced through the receptors when receptors of costimulatory molecules ligate to their ligands. However, recent studies demonstrated that some costimulators have been shown to potently costimulate T cell effectors function as measured by proliferation and cytokine production, while being capable of delivering bi-directional signals into APCs via their ligands. Bidirectional transduction of signals through the receptors as well as the ligands have been proved for the 4-1BB/4-1BBL, OX40/OX40L, CD27/CD27L, CD40/CD40L, CD95/CD95L, CD30/CD30L, etc. Therefore, the roles of the costimulaory molecules in immunoregulation are more complex than initially assumed.Human 4-1BB/4-1BBL belongs to TNF receptor/TNF superfamily. 4-1BB is a 30 kD type I transmembrane glycoprotein, which is expressed on the activated CD4~+and CD8~+T cells. When given in conjunction with a strong signal through the TCR, 4-1BB signals can synergize with CD28 signals to promote T cells activation, proliferation, cytolytic effector function, cytokine secretion, and prevents activation-induced cell death. CD28 is important for initial T cell expansion, whereas 4-1BB/4-1BBL signalling affects T cell numbers much later in the initial response and secondary response. Human 4-1BBL is a type II transmembrane glycoprotein. 4-1BBL is expressed on many types of cells, including IFN-activated macrophages, CD40 ligand-activated B cells, dendritic cells, monocytes, T cells or tumor cells. Recent studies revealed that bi-directional transduction of signals existed for the 4-IBB receptor/ligand system. While cross-linking of 4-IBB activates T...