Repertoire analyses reveal TCR sequence features that influence T cell fate

Abstract

T cells acquire a regulatory phenotype when their T cell receptors (TCRs) experience an intermediate-high affinity interaction with a self-peptide presented on MHC. Using TCR sequences from FACS-sorted human cells, we identified TCR features that shape affinity to these self-peptide-MHC complexes, finding that 1) CDR3β hydrophobicity and 2) certain TRBV genes promote Treg fate. We developed a scoring system for TCR-intrinsic regulatory potential (TiRP) and found that within the tumor microenvironment clones exhibiting Treg-Tconv plasticity had higher TiRP than expanded clones maintaining the Tconv phenotype. To elucidate drivers of these predictive TCR features, we examined the two elements of the Treg TCR ligand separately: the self-peptide via murine Tregs, and the human MHC II molecule via human memory Tconvs. These analyses revealed that CDR3β hydrophobicity promotes reactivity to self-peptides, while TRBV gene usage shapes the TCRs general propensity for MHC II restricted activation.

TCR-sequencing in cancer and autoimmunity: barcodes and beyond

“…In this way, sister clones can be tracked within or between tissues based on sharing of the TCR sequence [27][28][29]36,38,39,50,51]. Additionally, the TCR also acts as a set of features that influence T cell fate and function following antigen encounter [68,69,71]. In the figure, T cells (which can refer to either CD4 + or CD8 + T cells) with the same color TCR are considered clones based on matching sequences.…”

“…While these approaches demonstrated the predictive value of TCR amino acids in terms of tumor infiltration, the functional phenotype of these cells remained unknown. Focusing on T cell phenotypes, an orthogonal study from our group developed a TCR scoring system that ultimately described which CD4 + T cells in the TME were more likely to express a regulatory T cell (Treg) phenotype over a conventional effector CD4 + T cell phenotype (Tconv) based on features of the TCR sequence [71]. Training data for this scoring system used human circulating Tregs, which were expected to largely consist of clones that became Tregs in the thymus [72].…”

“…After developing the scoring system based on data from individuals without cancer, TILs were scored from basal and squamous cell carcinoma patients; T cell clones containing Tregs harbored significantly higher-scoring TCRs than other T cells. When the TCR was used as a barcode to mark clonally related cells, some T cell clones consisted of both Treg and Tconv cells [71]. These clones, likely consisting of peripherally induced Tregs and Tregs that have lost their suppressive phenotype (exTregs), also demonstrated significantly more Treg-like TCRs than clones that maintained the conventional effector phenotype [71].…”

“…When the TCR was used as a barcode to mark clonally related cells, some T cell clones consisted of both Treg and Tconv cells [71]. These clones, likely consisting of peripherally induced Tregs and Tregs that have lost their suppressive phenotype (exTregs), also demonstrated significantly more Treg-like TCRs than clones that maintained the conventional effector phenotype [71]. While the extent to which peripherally induced Tregs contributed to this result remains to be determined, the identification of TCR sequence features that could promote suppressive phenotypes in the tumor is an important step toward understanding the T cell population involved in the antitumor response.…”

“…While the extent to which peripherally induced Tregs contributed to this result remains to be determined, the identification of TCR sequence features that could promote suppressive phenotypes in the tumor is an important step toward understanding the T cell population involved in the antitumor response. These Treg-promoting TCR sequence features are also significantly enriched in TCRs known to be autoreactive [71], suggesting that such TCR scoring might be used to screen for autoimmune pathogenic TCRs, most of which have been elusive to date.…”