To Be or Not to Be—Thymocyte Survival and Death in the Thymic Medulla

The T cells of the mammalian immune system have a tricky challenge. They must recognize foreign antigen as “other” or “non-self” but in the context of self, while also being tolerant to the body’s own molecules and tissues. T-cell receptor (TCR) gene rearrangement occurs in the cortex of the thymus and generates receptors of relatively random specificity. The developing T cells (thymocytes) are screened in two stages, both of which are Major Histocompatibility Complex (MHC)-based. The first, positive selection, occurs in the thymic cortex where cortical thymic epithelial cells (cTECs) display self MHC + self-peptides. Thymocytes that can bind to self MHC + self-peptide then migrate to the corticomedullary junction, where they undergo negative selection. Here, they encounter antigenic peptides characteristic of peripheral tissue proteins presented by medullary antigen-presenting cells (APCs). Among the most intriguing APCs in the medulla are the mimetic medullary thymic epithelial cells (mimetic mTECs). These mimetic APCs express peripheral antigens under the direction of specific transcription factors. During negative selection, most thymocytes whose TCRs bind too well to self MHC + self-peptide die by apoptosis. However, a small proportion of autoreactive thymocytes escape negative selection and instead “alternatively” differentiate into specialized cell types that are self-tolerant and even enforce self-tolerance. The CD4 and CD8 coreceptors, which bind to MHC II and MHC I, respectively, play crucial roles in positive and negative selection. With CD8, there is an added level of complexity because there are two forms of CD8, only one of which can promote signaling through the TCR. Upon binding to MHC, CD4 and CD8 initiate signal transduction through the TCR. The strength of signal transduction through the TCR and through co-stimulatory CD28 determines the outcome of TCR-MHC + peptide binding. Signal transduction occurs within the immunological synapse and is regulated by kinetic proofreading mechanisms. In summary, negative selection involves interactions between developing thymocytes and a variety of medullary APCs. These molecular interactions occur at specialized membrane domains that bring together the components of the TCR signaling apparatus, which are subject to kinetic proofreading. Together, the regulatory mechanisms occurring in developing thymocytes and in medullary APCs generate a T-cell arsenal that is tolerant of self and active against foreign entities.