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Adaptive immune surveillance by human γδ T cells: implications for antimicrobial immunity

Human γδ T cells comprise ~10% of the T cell population in peripheral blood and in the tissues and are directly implicated in T cell receptor (TCR)-dependent anti-microbial and anti-tumour immunity. However, whether this unconventional T cell subset occupies an innate-like or adaptive immunological niche is unclear. We provide evidence that the TCR repertoire of tissue associated γδ T cells is private and initially unfocussed in cord blood, typically becoming strongly focussed towards a few high-frequency clonotypes by adulthood. Clonally expanding γδ subsets differentiated from a naïve to effector phenotype (γδ T effectors) associated with CD27 downregulation, retention of proliferative capacity and TCR sensitivity. γδ T effectors display increased cytotoxic markers and altered homing capabilities, with TCR clonality highly stable over time.

These adaptive γδ T cell subsets clonally expanded and differentiated in direct response to acute human viral infection. Consistent with an antimicrobial immunosurveillance role in the tissues, we found the tissue-infiltrating γδ T cell compartment to be predominantly clonally focussed, frequently dominated by expanded clonotypes featuring complex, private TCR rearrangements and displaying a γδ T effector phenotype.

Finally, clonally expanded tissue-associated γδ T cells displayed hallmarks of tissue residency (γδ T RM).These findings redefine human γδ T cell biology by indicating that tissue infiltrating γδ T cells predominantly comprise private clonally expanded subsets, suggestive of an adaptive immunobiology. Ultimately, these findings indicate a TCR-mediated γδ T cell immune surveillance network, potentially responding to microbial infections and malignancy.

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