The same self-peptide selects conventional and regulatory CD4+ T cells with identical antigen receptors

Abstract

The role of the T cell receptor (TCR) in commitment of thymocytes to regulatory CD4+Foxp3+ and conventional CD4−Foxp3− T cell lineages remains controversial. According to the prevailing view, commitment to the former lineage, in contrast to the latter, requires that high affinity TCRs bind rare class II MHC/peptide complexes presented in “thymic niches”, which could explain differences between their TCR repertoires. Here we challenge this view and show that the binding of identical TCRs to the same ubiquitously expressed MHC/peptide complex often directs thymocytes to both CD4+ lineages, indicating that the TCR affinity does not play the instructive role, and that restricted presentation of peptides in ”thymic niches” is not necessary for selection of CD4+Foxp3+ T cells. However, depending on whether immature thymocytes bound the ligand predominantly with low or high affinity, the repertoires of regulatory and conventional CD4+ T cells were correspondingly similar or mostly different, suggesting that negative rather than positive selection sets them apart.

Controversies concerning thymus‐derived regulatory T cells: fundamental issues and a new perspective

“…Repertoire studies, however, have not been conclusive to the self‐reactivity of tTregs. Some studies showed that Foxp3 + CD4 + T cells had a different TCR repertoire from Foxp3 − CD4 + T cells, 27 , 28 , 29 while others showed that TCR repertoires of Tregs and naive T cells were overlapping 30 and that the same peptide selected both Foxp3 + CD4 + T cells and Foxp3 − CD4 + T cells 31 . Similarly, repertoire studies only compared the bulk Foxp3 + and Foxp3 − CD4 + T cells and dismissed to analyse Foxp3 − CD4 + memory‐like T cells, which presumably experienced cognitive antigens.…”

Regulatory and T Effector Cells Have Overlapping Low to High Ranges in TCR Affinities for Self during Demyelinating Disease

“…It has been shown that thymocytes are able to develop into both Tregs and Tconvs by selecting on the same self peptide using the identical TCR (13). The limitations imposed by the selecting size niche did replicate when TCRs from three different tTreg cells were used to make retrogenic mice (7).…”

The mechanisms shaping the repertoire of CD4+ Foxp3+ regulatory T cells

“…This result shows that other factors, besides the TCR, determine thymocyte lineage commitment. Moreover, Treg cells expressing identical TCRs as naive CD4 + T cells continued to develop in mice expressing single, covalently linked class II MHC/peptide complexes, demonstrating that TCRs with the same affinity for the selecting ligand can be expressed by thymocytes differentiating to both CD4 + lineages . The proportion of Foxp3 + thymocytes in mice expressing a single class II MHC–peptide motif was smaller than in mice expressing wild‐type class II MHC–peptides, but surprisingly large considering the drastic restriction in diversity of selecting ligands.…”