Re-examining the Nature and Function of Self-Reactive T cells

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.

TrendsSelf-reactive T cells are present in significant numbers in otherwise healthy humans and mice. These cells are normally contained but have the potential to cause pathological autoimmune disease when peripheral tolerance mechanisms are alleviated (e.g., novel cancer immunotherapeutic strategies).T cell receptors are polyreactive. One TCR can recognize a wide array of pMHC complexes with different functional outcomes. Changes in the functional avidity of TCR:pMHC interactions may unleash previously tolerized self-reactive T cells.Not all self-reactive T cells are destructive. Self-reactive T cells can support such diverse processes as maintaining tissue homeostasis in the central nervous system, wound healing, and boosting immunity against infections. These functions can be summarized as physiological (beneficial) self-reactive. In this regard, these cells can perform similar functions as regulatory T cells.The mechanisms that restrain self-reactive T cells and instruct them to perform physiological functions are not understood.