The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function

Abstract

Self-reactivity was once seen as a potential characteristic of T cells that was eliminated by clonal selection to protect the host from autoimmune pathology. We now appreciate that the T cell repertoire is in fact, broadly self-reactive, one could even say self-centered. The strength with which a T cell reacts to self ligands, and the environmental context that this reaction occurs in, influences almost every aspect of T cell biology: from development to differentiation to effector function. In this review we highlight recent advances and discoveries that relate to T cell self-reactivity, with a particular emphasis on TCR signaling thresholds.

High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity

“…It is likely that CD5 expression is proportional to the net overall signal received by a T cell in response to several ligands. Therefore, CD5 might not always indicate a level of reactivity to a single self-peptide but rather the cumulative TCR signaling received during thymic selection (21). Nevertheless, we observed a direct correlation with CD5 and TCR-induced Nur77 GFP in islet-infiltrating Tregs ( Figure 1B).…”

“…Although, CD5 is considered to be the most faithful marker of self-reactivity described to date, specifically in the Tconv population, direct correlation between CD5 and the magnitude of Treg self-reactivity in tissue autoimmunity has not been assessed (20,21 ) cells confirmed previous observations that Tregs express higher levels of CD5, indicative of their general propensity for self-reactivity (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.97322DS1) (22). CD5 expression was higher on islet-infiltrating Tconvs and Tregs compared with cells obtained from peripheral draining lymph nodes (Supplemental Figure 1A).…”

A “hotspot” for autoimmune T cells in type 1 diabetes

“…For example, there are approximately 5 × 10 11 possible sequence combinations for a 9 amino acidlong peptide. Mature T cells are therefore equipped with TCRs that can recognize multiple distinct peptides, thus avoiding holes in the repertoire (1,2).…”

“…This developmental checkpoint puts a lower limit on the rate of peptide cross-reactivity, as TCRs have to engage at least 1/10,000 pMHC ligands with measurable binding affinity. Conversely, thymocytes that expresses TCRs that are unable to sufficiently distinguish different self-peptides or recognize any self-peptides with a strong affinity are signaled to undergo apoptosis (1,2). The fittest T cells -those that are most likely to provide broad immunological coverage while limiting overt self-reactivity -are ushered along the developmental pathway and are ultimately exported to become part of the mature T cell repertoire.…”

The adaptive immune response to Epstein-Barr virus

“…Recently it has been suggested that a crippling of the CD8 + T cell repertoire and domination by T cells with a high affinity to self antigens can result from interference in antigen processing in the cortical thymic epithelial cell-specific pathway that diversifies the T cell repertoire (Klein, Kyewski et al 2014). Another recent study has shown that mechanisms exist that allow T cells with low affinity for self ligands to avoid clonal deletion and apoptosis (Hogquist and Jameson 2014). It has also been suggested that nonstimulatory self peptide-MHC complexes may assist the reactivity of T cells to foreign peptide-MHC antigen (Krogsgaard, Juang et al 2007).…”