T-cell co Sample Clauses

T-cell co stimulation It was initially believed that TCR engagement with MHC was sufficient to induce activation of naïve T cells; however, experiments with primary T cell cultures proved that for optimal activation a second signal is required. This second signal comes from co- stimulatory molecules expressed by T cells binding to ligands on APCs. CD28 is the putative co-stimulatory molecule expressed by all T cells, and in the absence of signalling through CD28 T cells undergo anergy whereby they become unresponsive to antigen (82). The ligands for CD28 are CD80 and CD86, which are upregulated on APCs during inflammation. CD152 expressed on T cells can also bind CD80 and CD86 although with very different functional outcomes. CD152 is known as a co-inhibitory molecule as its engagement leads to down-regulation of CD80 and CD86 on APCs and thus a dampening of the immune response. Approaches for blocking co-stimulation in transplantation models have used CTLA-4Ig with success (83). This has now been developed into a clinical strategy with the development of Belatacept, a CTLA-4Ig drug available for human use that has been used as immunosuppressive therapy for renal transplantation patients (84). CD40 and its ligand CD154 are essential co-stimulatory molecules for the effective generation of high affinity isotype-switched antibodies. CD40/CD154 interactions are also important for DC survival, proliferation of B cells and activation of some antigen- specific T cells. Efforts to translate anti-CD154 therapy into the clinic was unfortunately halted, despite promising results in pre-clinical models, due to the expression of CD154 on activated platelets which led to adverse thromboembolic effects in treated individuals (85). The programmed death (PD) 1 receptor is expressed on many cells of the immune system including NK cells and some DCs, and binds the ligands PDL1 and PDL2. It is not constitutively expressed on T cells but is up-regulated following activation, and ligation leads to down-regulation of T cell effector cytokines such as IFN-γ, TNF-α, and IL-2. This pathway has also shown importance in transplantation with PD1 knock-out recipients overcoming co-stimulation blockade-induced tolerance (86). As yet there are no reagents available for the activation of PD1 in humans, although recent efforts to switch off this pathway for the treatment of cancer have demonstrated its importance in human immune responses (87).
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