Book Description

During T cell development, most cells with high avidity for self-antigen are deleted in the thymus through a process termed negative selection or central tolerance. However, due to variations in the level of antigen expression and availability, not all auto-reactive T cells may encounter their cognate antigen under the proper conditions to promote their elimination. Therefore, additional mechanisms are required to induce tolerance in the peripheral lymphoid organs such as the lymph nodes and spleen. This, process, called peripheral tolerance, provides another level of protection against the activation of auto-reactive T cells. T cell peripheral tolerance occurs through a variety of mechanisms including clonal elimination, the induction of non-responsiveness, TCR down-regulation, increased expression of negative signaling molecules, or immuno-regulation. Importantly, recent studies have demonstrated that defects in either central or peripheral T cell tolerance can contribute to the development of autoimmune diseases, such as type 1 diabetes and multiple sclerosis. Consequently, it is critical to understand the mechanisms underlying T cell peripheral tolerance in order to develop better therapies for the treatment and prevention of autoimmunity. To this end, the mechanisms promoting CD8 T cell peripheral tolerance to both cross-presented self-antigen and soluble peptide were examined. The deletion of naïve CD8 T cells following tolerogenic stimulation was found to occur independently of a death signal and, rather, required the sustained presence of antigen. Further studies revealed that depending upon the dose and kinetics of antigen treatment, tolerized CD8 T cells could undergo either apoptotic death or become functionally non-responsive, or anergic. The induction and maintenance of anergy required high levels of persistent antigenic stimulation and correlated with the down-regulation of TCR-mediated signaling molecules. In contrast, low levels of chronic antigen stimulation led to clonal elimination of the responding T cells. These data provide insight into the role of chronic antigen in the induction of CD8 T cell peripheral tolerance. Finally, the mechanism of naïve CD8 T cell deletion during peripheral tolerance was found to occur via an intrinsic apoptotic mechanism that could be inhibited by expression of the anti-apoptotic molecule, Bcl-2.