Systematic pattern analyses of Vδ2+ TCRs reveal that shared "public" Vδ2+ γδ T cell clones are a consequence of rearrangement bias and a higher expansion status

Front Immunol. 2022 Sep 27:13:960920. doi: 10.3389/fimmu.2022.960920. eCollection 2022.

Abstract

Background: Vγ9Vδ2+ T cells are a major innate T cell subset in human peripheral blood. Their Vδ2+ VDJ-rearrangements are short and simple in the fetal thymus and gradually increase in diversity and CDR3 length along with development. So-called "public" versions of Vδ2+ TCRs are shared among individuals of all ages. However, it is unclear whether such frequently occurring "public" Vγ9Vδ2+ T cell clones are derived from the fetal thymus and whether they are fitter to proliferate and persist than infrequent "private" clones.

Methods: Shared "public" Vδ2+ TCRs were identified from Vδ2+ TCR-repertoires collected from 89 individuals, including newborns (cord blood), infants, and adults (peripheral blood). Distance matrices of Vδ2+ CDR3 were generated by TCRdist3 and then embedded into a UMAP for visualizing the heterogeneity of Vδ2+ TCRs.

Results: Vδ2+ CDR3 distance matrix embedded by UMAP revealed that the heterogeneity of Vδ2+ TCRs is primarily determined by the J-usage and CDR3aa length, while age or publicity-specific motifs were not found. The most prevalent public Vδ2+ TCRs showed germline-like rearrangement with low N-insertions. Age-related features were also identified. Public Vδ2+ TRDJ1 TCRs from cord blood showed higher N-insertions and longer CDR3 lengths. Synonymous codons resulting from VDJ rearrangement also contribute to the generation of public Vδ2+ TCRs. Each public TCR was always produced by multiple different transcripts, even with different D gene usage, and the publicity of Vδ2+ TCRs was positively associated with expansion status.

Conclusion: To conclude, the heterogeneity of Vδ2+ TCRs is mainly determined by TRDJ-usage and the length of CDR3aa sequences. Public Vδ2+ TCRs result from germline-like rearrangement and synonymous codons, associated with a higher expansion status.

Keywords: TCR distance; TCR sequencing; TRD rearrangement; Vγ9Vδ2+ T cells; γδ TCR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Clone Cells
  • Humans
  • Infant
  • Infant, Newborn
  • Intraepithelial Lymphocytes*
  • Receptors, Antigen, T-Cell, gamma-delta* / genetics
  • T-Lymphocyte Subsets
  • Thymus Gland

Substances

  • Receptors, Antigen, T-Cell, gamma-delta