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

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.

Figure 1. Functional responses following TCR:pMHC engagement in healthy conditions and situations with altered peripheral tolerance.

(A) In healthy individuals, weak signals produced by engagement of TCRs with self-peptide/MHC complexes (self-Ag) can result in multiple beneficial responses ranging from survival (maintenance ligand; on the single cell level) to supporting tissue homeostasis and foreign antigen responses (poly-reactive TCRs). While strong self-peptide/MHC induced TCR signals lead to anergy. (B) In situations where peripheral tolerance mechanisms have been altered, such as cancer immunotherapy or Treg cell depletion, the functional avidity of TCR:pMHC interactions will be changed. This might shift the activation threshold and lead to the emergence of destructive autoimmune diseases. For example, a previously non-functional T cell can now be activated by a ubiquitous self-Ag or a physiological self-reactive T cell could be converted into a pathological self-reactive T cell.

Figure 2. Differentiation between self-reactive T cells.

While the different groups of self-reactive T cells may be impossible to discriminated based on TCR specificity, they have unique functional outcomes. Except for Treg cells, little is known about the unique phenotypic characteristics of physiological and pathological self-reactive T cells, such as transcription factors (TF) or surface protein expression patterns. The most promising line of research could involve looking for evidence of anergy in potential pathological self-reactive T cells.