Only a few direct TCR ligands were identified to date. This was in part because, in contrast to αβ T cells that recognize peptide antigens in a conserved MHC-restricted mechanism, ligands and factors that shape the γδ TCR repertoire and activation remained largely enigmatic. However, the number of clonotypes found in an individual’s γδ TCR repertoire is probably much smaller, and the composition of human γδ TCR repertoires in health and disease is an active field of research.įor a long time, the general understanding of γδ T cell biology was that γδ T cells are innate-like T lymphocytes, similar to invariant natural killer T (NKT) or mucosa-associated invariant T (MAIT) cells. Therefore, all γδ T cells together possess a large repertoire of unique TCRs, termed clonotypes, that in theory could comprise up to 10 18 TRG/TRD combinations. Next to a multiplication of the potential TCR variety by the pairing of TRG and TRD chains, overall diversity is greatly amplified by junctional diversity, through the insertion of palindromic sequences (P nucleotides) and of non-templated nucleotides by the terminal deoxynucleotidyl transferase (TdT) enzyme (N nucleotides) at the V(D)J junction (CDR3 region). The genes encoding TRG and TRD rearrange during γδ T cell maturation in the thymus.īriefly, the somatic DNA recombination of variable (V), diversity (D, only in TRD), and joining (J) elements creates combinatorial diversity of the individual TCR chains, a process called V(D)J-recombination. First, the defining characteristic of the γδ T lymphocyte subset is their specific T cell receptor (TCR), composed of a γ-chain (TRG) and a δ-chain (TRD). The biology of γδ T cells in blood and tissues is incompletely understood, although they exert pleiotropic functions such as cytokine production, tissue regulation, B cell help and cytotoxicity. Γδ T cells are detected at frequencies of 3–10% of T cells in the peripheral blood of human adults and are often enriched as resident cells within solid organs and mucosal tissues. We discuss the current understanding of clonal composition and the dynamics of human γδ TCR repertoires in health and disease. Here, we review how the recent introduction of high-throughput TCR repertoire sequencing has boosted our knowledge of γδ T cell repertoire diversity beyond Vδ2 + and Vδ1 + T cells. Yet, this distinction into innate-like Vδ2 + and adaptive-like Vδ1 + γδ T cells does not quite recapitulate the full diversity of γδ T cell subsets, ligands and interaction modes. Of those two subsets, Vδ2 + T cells seem to better fit into a role of innate T cells with semi-invariant TCR usage, as compared to an adaptive-like biology of some Vδ1 + subsets. Most of our current knowledge of human γδ T cell receptor diversity builds on specific monoclonal antibodies that discriminate between the two major subsets, namely Vδ2 + and Vδ1 + T cells. While the theoretical TCR repertoire diversity of γδ T cells is estimated to exceed the diversity of αβ T cells by far, γδ T cells are still understood as more invariant T cells that only use a limited set of γδ TCRs. The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ T cells.
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