Oral Presentation Lorne Infection and Immunity 2019

Adaptive immune surveillance by human γδ T cells in microbial infection (#33)

Martin S Davey 1 , Anouk von Borstel 1 , Lauren J Howson 2 , Daniel Arsovski 1 , Jamie Rossjohn 1 , Carrie R Willcox 2 , Ye H Oo 2 , Benjamin E Willcox 2
  1. Monash University, Clayton, VIC, Australia
  2. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK

Human γδ T cells comprise around 10% of the T cell population in the peripheral blood and tissues. Human γδ cells have been implicated in T cell receptor (TCR)-dependent anti-microbial and anti-tumour immunity. However, the immunobiology of tissue-associated γδ subsets and the immunological niche these unconventional T cell subsets occupy is largely unknown. We provide evidence that the TCR repertoire of tissue associated γδ T cells follows a TCR-dependent adaptive pathway, that is private and initially unfocussed in cord blood, typically becoming strongly focussed towards a few high-frequency clonotypes by adulthood. Clonal expanded γδ T cells had differentiated from a naïve to effector phenotype associated with CD27 down-regulation, retention of proliferative capacity and TCR sensitivity.  γδ T effectors displayed increased cytotoxic markers and altered homing capabilities, and TCR clonality was highly stable over time. Moreover, we identified a novel γδ T effector subset present in adult peripheral blood at frequencies equivalent to invariant Natural Killer T cells. This subset underwent dramatic clonal expansion and differentiation in response to acute viral infection in kidney transplant patients. Consistent with a viral immune surveillance role in the tissues, we frequently found human liver-associated γδ T effector featuring dominant clonal expansions. These dominant clonotypes segregated into both circulating and liver-resident populations. These data suggest that the ability of γδ T cells to undergo clonotypic expansion and differentiation is crucial in permitting access to solid tissues, such as the liver. Together, these findings redefine our understanding of human γδ T cell subsets by demonstrating that tissue infiltrating γδ T cells predominantly comprise clonally expanded subsets, suggestive of an adaptive immunobiology.