NKp46+CD3+ T-Cells As A Novel Target For Vaccines Against bovine TB

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Bovine tuberculosis (bTB) is the most important disease affecting the UK cattle industry. Failure of the current 'test-and-slaughter' policy to constrain the spread of bTB has led to a review of what strategies should be implemented in future to improve the control of this disease. BCG, the only licensed bTB vaccine, exhibits variable and unpredictable levels of protection and is not DIVA compliant so can't be used in current disease control programmes. Consequently, there is a need to develop vaccines that confer more reliable immunity and can be integrated with bTB field surveillance. Development of such vaccines requires a better understanding of i) the components of the immune response that contribute to protective immunity and ii) how immune responses can be exploited to discriminate between vaccinated and Mb-infected animals. Although it is well established that protective immunity against TB is cell mediated, the precise protective immunological mechanisms are still undefined. Evidence indicates that conventional peptide-MHCII restricted CD4+ T cell responses are critical for immunity and that for optimal anti-TB immunity peptide-MHCI restricted CD8+ T-cells are also required. In humans a large proportion of the cellular anti-TB response if composed of non-conventional lipid-specific CD1-restricted T-cells; the range of anti-mycobacterial effector functions exhibited by these cells indicates that they also contribute to host defence against TB. Consequently, it has been proposed that lipids may constitute novel antigens that could be used to enhance the immunogenicity and efficacy of next-generation TB vaccines. Lipids are attractive vaccine candidates as they i) activate both innate-like and adaptive T-cell responses, ii) can have adjuvant properties and iii) are presented by non-polymorphic CD1 genes and therefore (unlike MHC-restricted peptides) have utility across an outbred population. In addition, some lipids don't induce responses against PPD, so could be used as DIVA reagents. Although cattle lipid-specific T-cell responses have been reported in bTB, knowledge of their role in anti-bTB immunity is negligible. Recent studies conducted by our laboratories have identified a novel population of non-conventional NKp46+CD3+ bovine T-cells and demonstrated that a subset of these cells respond to PIM, a group of lipids from M. bovis in a proportion of Mb-infected animals. In this project we propose to gain information on lipid-specific T-cell responses in bTB by analysing NKp46+CD3+ T-cells during a BCG-immunisation/Mb-challenge study. We will also perform studies to identify the range of antigenic TB lipids and determine which are immunogenic and so could contribute to new effective bTB vaccines. The objectives of the project are to:1. Quantify and track the NKp46+CD3+ T-cell responses following BCG vaccination and subsequent exposure to M. bovis. This will help determine if NKp46+CD3+ T-cells are functioning as innate and/or adaptive effector T-cells and if BCG immunisation forms a memory population recalled during Mb challenge.2. Examine the function of NKp46+CD3+ T-cells recognising mycobacteria. This will define the role of NKp46+CD3+ T-cells in anti-TB immunity. Data from objectives 1 and 2 will also be used to examine if NKp46+CD3+ T-cell responses correlate with anti-bTB protection conferred by BCG immunisation.3. Identify additional mycobacterial lipids that could be used to generate NKp46+CD3+ (and other) bovine T-cell responses. It is likely that multiple TB lipids will be antigenic in cattle and that some lipid-specific T-cells may lie out-with the NKp46+CD3+ T-cell subset. This study will expand the knowledge of the bTB lipid antigen repertoire (and also determine if any could be exploited for DIVA applications).4. Identify which mycobacterial lipids elicit NKp46+CD3+ T-cell responses in vivo. This will establish which lipids are immunogenic in vivo and are therefore genuine vaccine candidates.