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Molecular design of the γδ T cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing

ABSTRACT: High acuity αβT cell receptor (TCR) recognition of peptides bound to MHC molecules (pMHC) requires mechanosensing, a process whereby piconewton (pN) bioforces exert physical load on αβTCR-pMHC bonds to dynamically alter their lifetimes and foster digital sensitivity cellular signaling. While mechanotransduction is operative for both αβTCRs and preTCRs within the αβT-lineage, its role in γδT cells is unknown. Here we show that the human DP10.7 γδTCR specific for the sulfoglycolipid sulfatide bound to CD1d only sustains significant load and undergoes force-induced structural transitions when the binding interface-distal γδ constant domain (C) module is replaced with that of αβ. The chimeric γδ-αβTCR also signals more robustly than the wild-type γδTCR as revealed by RNA-seq analysis of TCR-transduced Rag2-/- thymocytes, consistent with structural, single molecule and molecular dynamics studies reflective of γδTCRs as mediating recognition via a more canonical immunoglobulin-like receptor interaction. Absence of robust, force-related catch bonds as well as γδTCR structural transitions implies that γδT cells do not use mechanosensing for ligand recognition. This distinction is consonant with the fact that their innate-type ligands, including markers of cellular stress, are expressed at high copy number relative to sparse pMHC ligands of αβT cells arrayed on activating target cells. We posit that mechanosensing emerged over ~200 million years of vertebrate evolution to fulfill indispensable adaptive immune recognition requirements for pMHC in the αβT cell lineage that are unnecessary for the γδ T cell lineage mechanism of non-pMHC ligand detection.

ORGANISM(S): Mus musculus

PROVIDER: GSE165297 | GEO | 2021/06/22

REPOSITORIES: GEO

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Project description:The immune system consists of a network of specialized cells and processes that protect the organism from diseases and regulates tissue repair. Natural killer (NK) cells and the αβ and γδ T cells comprise the cytotoxic arm of the immune system and have evolved to detect and eradicate cells infected with pathogens and affected by malignancies, in order to prevent their spread and subsequent tissue damage. The naked mole-rat (NMR; Heterocephalus glaber) exhibits an unusually long lifespan relative to its body size, remarkable cancer resistance, and a surprising absence of NK cells, likely lost during its evolution. So far, little is known about NMR T cells in terms of the subsets they comprise, the evolution of the genes that regulate their function, the diversity of their clonotypes, and the organ in which they mature – the thymus. Using single-cell RNA sequencing (scRNA-seq), we find that NMRs have a large population of circulating γδT cells, comprising two subsets, one with an activated cytotoxic profile. Using comparative genomics, we find that the NMR genome maintains a large diversity of γ and δ variable T-cell receptor (TCR) regions, relative to that in other mammalian genomes. We devise a novel TCR scRNA-seq approach, which reveals that the NMR cytotoxic γδT-cell subset harbors a dominant clonotype, and that, in contrast to mouse, the clonotypic diversity of NMR CD8 αβT cells is significantly lower than that of its CD4 αβT cells. The latter suggests that NMRs have evolved under a relaxed intracellular pathogenic selective pressure, consistent with the loss of their NK cells. We corroborate this by showing that the genomic diversity of NMR MHC-I genes, relative to that of MHC-II genes, is considerably smaller than in other mammalian genomes. In line with these findings, we further show that NMR thymi in early life are considerably smaller compared to mouse thymi, yet by middle age thymi of both species show equivalent signs of involution. Our study thus sheds significant light on NMR T cells and moves us one step closer towards understanding the contributions of the immune system to the remarkable longevity and cancer resistance of this species.

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Molecular design of the γδ T cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing

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