Human γδ TCR Repertoires in Health and Disease.

Alina Suzann Fichtner,Sarina Ravens,Immo Prinz

doi:10.3390/cells9040800

Abstract

The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ 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. 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. 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. 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. 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. We discuss the current understanding of clonal composition and the dynamics of human γδ TCR repertoires in health and disease.

Highlights

Introduction γδT 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 [1,2,3]
To a multiplication of the potential T cell receptor (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) [6]
The development of several waves of γδ T cell subsets, such as Vγ5Vδ1 dendritic prewired to become IL-17 producers even before TCR expression [57,58], a strong TCR-signal epidermal T cells (DETCs) or Vγ6Vδ1+ IL-17-producing γδ T cells, exclusively takes place in the fetal mediated via Skint1, a butyrophilin-like molecule expressed on thymic epithelial cells, will induce thymus and these cells are maintained as long-lived effector cells after birth [23,24]

Summary

Human γδ T Cell Subsets Are Defined by Their TCR δ Chain

Tissue localization and effector function of γδ T cells is typically correlating to their expressed TCR γ chain. Via Skint, a butyrophilin-like molecule expressed on thymic epithelial cells, will induce the IFN-γ [59] Later in gestation, both Vδ1+ and Vδ2+ TCRs can be detected, with a prominence of Vδ2+ chains phenotype of Vγ5Vδ1+ DETCs during thymic development. Vδ1 TCR are characterized by a semi-invariant Vγ9Vδ2+ TCR with characteristics of pAg-reactive TCRs, like rearrangements dominate the fetal thymus γδ T cell receptor sequences Indicating a first wave of Vγ9Vδ2+ T cells before gestational week 30 [62] These fetal Vγ9Vδ2+ T cells (translation: “CALWEVQELGKKIKVF”), formed without the addition of N nucleotides, but using are characterized by a semi-invariant Vγ9Vδ2+ TCR with characteristics of pAg-reactive TCRs, like short homology repeats (GCA) [28,62]. The fact that fetal non-Vγ9Vδ2+ T cells (in particular one Vγ8Vδ1+ T cell clone) can already mount efficient immune responses against in utero cytomegalovirus (CMV) infections [37] supports the idea that γδ T cells are an important innate immune cell subset during fetal life and in neonates

Development and Maintenance of γδ T Cells in Child- and Adulthood

Impact of Infectious Diseases on γδ TCR Repertoires

Viral Infections

Bacterial Infections

Parasitic Infections

Findings

Tissue-Resident γδ TCR Repertoires