Characterisation of cellular responses to pandemic influenza in naturally infected individuals

Abstract

Understanding the relevance of T cells in limiting influenza illness severity will facilitate the rational design and evaluation of T cell-based universal influenza vaccines. The aim of this thesis was to characterise pre-existing T cell responses to influenza and follow the kinetics of these T cell responses to infection by exploiting the 2009 H1N1 pandemic (pH1N1). Peripheral blood mononuclear cells (PBMCs) were collected from healthy adults naïve to pH1N1 who were longitudinally followed over 2 influenza seasons from 2009 – 2011. Ex vivo pH1N1-specific memory CD4+ and CD8+ T cell responses were characterised by IFN-γ/IL-2 fluorescence-immunospot and 14-colour flow cytometry. In pH1N1 seronegative adults in a community setting, pre-existing influenza-specific T cells cross-reacting with pH1N1 were prevalent, pre-dominantly of a single-cytokine positive (IFN-γ+, IL-2+ or TNF-α+) and effector memory (CD45RA-CCR7-) or late effector (CD45RA+CCR7-) phenotype and expressed lung homing receptor (CCR5+) and cytotoxic degranulation marker (CD107ab+). Pre-existing CD8+IFN-γ+IL-2- Temra (CD45RA+CCR7-) cells limited disease severity following incident pH1N1 infection in the absence of protective strain-specific antibodies. Furthermore, we show that this protection-associated T cell subset is durably maintained in the absence of re-infection up to 1.5 years post-infection. The identification of a protection-associated immune correlate, the frequencies of which were increased and durably maintained by natural infection, is highly relevant for the development of a universal influenza vaccine inducing long-lasting, protective T cells.