Adjusting to self in the thymus: CD4 versus CD8 lineage commitment and regulatory T cell development

This review covers recent advances in our understanding of how developing T cells sense and adjust to their self-reactivity and how this impacts their decision to become a CD8 T cell, a CD4 T cell, or a regulatory T cell. During thymic development, thymocytes adjust their TCR response based on the strength of their reactivity to self-peptide MHC complexes. This tuning process allows thymocytes with a range of self-reactivities to survive positive selection and contribute to a diverse T cell pool. In this review, we will discuss recent advances in our understanding of how thymocytes tune their responsiveness during positive selection, and we present a "sequential selection" model to explain how MHC specificity influences lineage choice. We also discuss recent evidence for cell type diversity in the medulla and discuss how this heterogeneity may contribute to medullary niches for negative selection and regulatory T cell development.