Title: NKp46+CD3+ cells as a novel target for vaccines against bovine TB.
Funder: Department for Environment, Food and Rural Affairs

Abstract: Description 1. Policy context: The most cost-effective control measure for infectious disease is vaccination, and used alongside existing control measures, cattle vaccination could reduce bTB transmission and disease severity. The development of improved vaccines for cattle forms part of the Government’s comprehensive eradication strategy for bTB but is impeded because the mechanisms by which protection can be achieved are not fully understood. 2. Aims: We aim to address these problems by defining the role of non-conventional T cell sub-populations post-vaccination and challenge, and by identifying the mycobacterial ligands they recognise. This will elucidate the role of NKp46+CD3+ T cells in protection and the antigens they respond to, facilitating the rational design of novel subunit vaccines that may improve BCG efficacy and/or do not sensitise skin test reactivity. Alternatively provide antigens that support the DIVA skin test scenario. Non-conventional T-cell populations such as NKT and MAIT cells occupy a unique niche bridging innate and adaptive immunity and have been demonstrated to have a multitude of roles in coordinating immune responses against microbial infections.3. Hypotheses and research questions addressed: We postulate that these cells play a critical role in host defence against bTB and that targeting their responses, for example by inclusion of lipid antigens, in novel vaccination strategies, could enhance vaccination efficacy. In this study we propose to characterise responses of NKp46+CD3+ cells following BCG vaccination and subsequent M. bovis challenge and to address the following questions: 1. What are the quantitative and kinetic characteristics of the NKp46+CD3+ response following vaccination and exposure to M. bovis? 2. What are the functions of NKp46+CD3+ cells recognising mycobacteria? 3. What are the mycobacterial antigens recognised by NKp46+CD3+ cells? 4. Can mycobacterial lipid and glycolipid extracts elicit NKp46+CD3+ responses in vivo?4. Potential outcomes: a) More detailed appreciation of immune responses to BCG vaccination and M. bovis infection by defining the role of non-conventional T-cells in protection and disease; b) Identification of new antigens, for inclusion either in a subunit vaccine or in a DIVA skin test; c) Contribute to the toolbox required to rationally design and develop novel bTB vaccines or DIVA tests. Objective The Morrison and Vordermeier laboratories have recently identified a novel NKp46+CD3+ non-conventional T-cellpopulation in cattle and demonstrated that a subset of these cells recognise phosphatidylinositol mannosides (PIMs - agroup of membrane bound lipids) from Mb. In this project we propose to i) examine NKp46+CD3+ T-cell responses duringa BCG-immunisation/Mb-challenge study so as to gain some insights into the role of lipid-specific T-cells in bTB and ii)explore the breadth of lipids from TB that act as antigens for bovine T-cells and evaluate their potential as vaccineantigens. Specifically we aim to address the following questions:1. What are the quantitative and kinetic characteristics of the NKp46+CD3+ T-cell response following BCG vaccination andsubsequent exposure to M.bovis?2. What are the functions of NKp46+CD3+ T-cells recognising mycobacteria?3. Which mycobacterial lipids are recognised by NKp46+CD3+ (and other) bovine T-cells?4. Can vaccination with mycobacterial lipid extracts elicit NKp46+CD3+ T-cell responses in vivo?The combined results of the proposed studies will provide the fundamental basic immunological data to determine ifinclusion of lipid antigens has the potential to enhance the immunogenicity and protective efficacy of new bTB vaccines.We also will perform analyses to define if lipid antigens could be used as novel DIVA reagents.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION