The immunobiology of human hepatic gamma delta T cells

Hunter, Stuart (2018). The immunobiology of human hepatic gamma delta T cells. University of Birmingham. Ph.D.

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Abstract

The liver contains a number of tissue-associated lymphocyte populations, of which many have been implicated in the pathogenesis of chronic liver diseases. $\gamma\delta$ T cells, particularly the $V\delta2^{neg}$ subset, are known to comprise a substantial proportion of tissue-associated lymphocytes, although their immunobiology remains poorly understood. Here, the localisation, TCR diversity, immunophenotype and function of human intrahepatic $\gamma\delta$ T cells was explored with an emphasis on highlighting any potential role in chronic liver disease and also to further understanding of tissue-associated $\gamma\delta$ T cells, using the liver as a model tissue. Intrahepatic $\gamma\delta$ T cells were predominantly localised in the sinusoids and did not increase in frequency with chronic inflammation. $V\delta2^{neg}$ cells exhibited private TCR clonal focussing, with complex CDR3 regions suggestive of antigen-driven expansions, concordant with a loss of naive-like $CD27^{hi}$ cells present in the periphery. Expanded clonotypes were phenotypically $T_{EM}$ - or $T_{EMRA}$ -like, with $T_{EMRA}$ -like clonotypes shared between liver and blood and resembling vasculature-associated virus-specific $CD8^+$ T cells while $T_{EM}$ clonotypes were identified only in the liver and resembled tissue-resident $CD8^+$ T cells. These findings suggest that disease has minimal impact on intrahepatic $\gamma\delta$ T cells, while supporting an adaptive paradigm for these cells in the formation of tissue-associated subsets.