| Background: Optimal activation of antigen-specific lymphocytes requires specific antigen recognition by lymphocytes ('signal 1') and additional signals (called 'signal 2' or costimulatory signals). In the absence of signal 2, lymphocytes fail to respond effectively and are rendered anergic. Signal 1 is provided by the interaction of the peptide- antigen-MHC complex with the T-cell receptor (TCR). Signal 2 is delivered to T cells by co-stimulatory cell surface molecules expressed on APCs. Costimulation is of therapeutic interest because the manipulation of co-stimulatory signals might provide a means either to enhance or to terminate immune responses. The CD28/CTLA-4-B7-1/B7-2 pathway is the best characterized T-cell costimulatory pathway and is crucial in T-cell activation and tolerance. In conjunction with signaling throughthe T cell receptor, CD28 ligation increases antigen specific proliferation of T cells, enhances production of cytokines, stimulates differentiation and effector function, and promotes survival of T cells. In contrast, signaling through CTLA-4 is thoughtto deliver a negative signal that inhibits T cell proliferation, IL-2 production, and cell cycle progression. However, although the importance of both CD28 and CD154 in primary T cell activation is well established, these molecules appear to be far less important in the generation and maintenance of memory and effector T cell functions.For example, CD28 knock out mice still preserved normal immune response, and although blockade of costimulation with mAB of CD154 prolongs allograft survival, chronic rejection follows. These results suggests that during the late phase of IR, costimulation of CD28 is not essenstail and even not important, and there should exist additional active key costimulatory pathways in vivo.During last decade,Several new costimulatory molecules, including 4-1BB, CD40, OX40, CD27, ICOS and ICOS have been identified. Those papers argued that the immune response is a dynamic process and costimulatory signals can also be delivered to antigen-experienced T cells.It can be said that B7-1/B7-2—CD28/CTLA-4 and CD40L-CD40 pathway is important in activation of na?ve T cells,while other moleculars take CD28/CTLA4's place in late phase of T cells activation. Among these several newly identified moleculars,ICOS attract our attention for its significant role in the later response of T cells activation and the function maintenanceof the activated T cells. (Including memory and effector T cells)Inducible costimulator (ICOS) is the third member of the CD28 family. Unlike CD28,ICOS is expressed preferentially by activated T cells,and can be induced by antigen stimulation. The ICOS ligand was identified as being the third B7 family member and was termed B7 homolog (ICOSL); it is constitutively expressed by B cells, with lower expression on monocytes. Studies of ICOS show that ICOS costimulation is necessary for the activation and function of effector T cells,maintain of memeory T cells,and it plays a key role on these antigen-experience T cells' proliferation, lymphocytes trafficking, secretion of cytokines and chemokines. It can also upregulate the expression of CD40L and has a indirect reinforcement on the activated effection elicited by CD40L cosyimulation. These findings suggest that the function effect of memory and effector T cells are ICOS dependent.Objection: To further explore the regulatory mechanisms and other biological functions of ICOS through manipulating the ICOS-ICOSL pathway, we constructed the ICOSIg souble protein. If the souble ICOSIg engages ICOSL to block the cross-linking of ICOS and inhibit effection of activated T cells, it provides us a chance to study its role in immune regulation ,kinetics and signal transduction.Methods: To achieve this goal, we conducted the following works:1. The construction of hICOS eukaryotic expression plasmids⑴ The total length human ICOS cDNA was cloned from a normal human activated T cells cDNA library phAD.CAD with PCR, and its open reading frame is c... |
PDF Full Text Request