Abstract
Recent studies have leveraged MHC tetramer and TCR sequencing approaches towards a more precise characterization of the peripheral T cell repertoire, providing important insight into both the contribution of self-reactive T cells to the overall repertoire and their function. The peripheral T cell repertoire of healthy individuals contains a high frequency of diverse, self-reactive T cells. Furthermore, self-reactive T cells can perform essential beneficial physiological functions. We review these recent findings here, and discuss their implications to the current understanding of peripheral tolerance and the role of self-reactive T cells in autoimmune disease. We outline gaps in understanding, and argue that an important step forward is to revise the definition of self-reactive T cells to incorporate new concepts regarding the nature and physiological functions of different populations of T cells capable of recognizing self-antigens.