Induction of autoimmune pathology linked to asymmetric T cell division (63.21)

Abstract

Abstract Immunological tolerance, defined as the ability to distinguish between self and nonself, begins in the thymus where T cells undergo development. The affinity between T cell receptor (TCR) and pMHC has long been established as a major determinant guiding thymocyte selection and recent data revealed a universal threshold affinity used by all thymocytes with class I MHC restricted TCRs to initiate self tolerance. Nevertheless, the prevalence of autoimmune disease indicates that self reactive T cells can be activated in the periphery. Whether the affinity threshold established during thymic selection plays a role in the maintenance of peripheral self tolerance has not been established. Here we show that only high affinity ligands (above the threshold for negative selection) are able to induce disease in a mouse model of autoimmune diabetes. Immunization with high affinity peptides results in more efficient T cell-APC conjugate formation, T cell proliferation, VLA-4 upregulation and ultimately pancreatic infiltration. Importantly, higher affinity peptides are more efficient at inducing asymmetric cell division resulting in a greater number of fully differentiated effector T cells. In contrast, stimulation with low affinity peptides results in fewer asymmetric divisions and fewer effector T cells capable of promoting disease. These findings underscore the critical importance of TCR in directing T cell fate and maintaining peripheral T cell tolerance.