Transcriptional landscape of human blood monocyte and dendritic cell subsets at steady state and upon vaccination.

Abstract

Influenza virus remains a major global public health concern that causes annual epidemics and occasional pandemics. The best way to prevent infection is by vaccination. Vaccines work through the generation of protective antibodies against hemagglutinin. Whereas a majority of people respond to vaccination by generating neutralizing antibodies, some vulnerable populations fail to respond including young children, the elderly and immunocompromised people. The reasons for this lack of response to influenza vaccination are under intense study. Ideally, the adaptive immune response to influenza vaccine should include helper CD4⁺ T cells that can help B cells produce antibodies and CD8⁺ T cells that can eliminate infected cells. These responses are elicited and regulated by antigen presenting cells (APCs) such as dendritic cells (DCs). DCs capture antigens and present them to T and B lymphocytes leading to generation of cellular and humoral immunity. This study aims to identify a transcriptional signature of APCs to predict vaccine responsiveness. Using systems biology approaches, we examined transcriptional profiles of APCs, including monocyte and DC subpopulations, in order to identify signatures in vaccination response. We measured the transcriptional profiles of APCs at steady state, post vaccination, and potential correlation with development of immune response defined by antibody titers. We determined that the early innate immune response to the influenza vaccination peaks at day one after vaccine administration with a prominent type I interferon (IFN) signature contributed by monocytes and CD1c⁺ DCs. We found that monocytes and CD2⁺ pDCs were the main contributors to global transcriptional changes. Finally, we established transcriptional signatures at baseline that correlated with the magnitude of serological response to vaccination. Thus, this dissertation offers a proof-of-concept that transcriptional profiles of APCs at baseline might enable the identification of people who do not respond to influenza vaccination and therefore are at greater risk for infection. Larger studies are needed to confirm these pilot observations; however this work provides a framework for evaluating strategies aimed at the improvement of vaccination outcomes, such as the combination of vaccine with additional adjuvants.