T cells in tuberculosis: What type of T cell mediates immunity and how do we induce it by vaccination?

Vaccination is a powerful tool against disease but we have stalled in development of vaccines against some diseases. The reason for this failure is that we do not understand how the immune response, which is the target of the vaccine, actually controls these diseases. Tuberculosis (TB) is one such disease despite the current vaccine, BCG, being the most widely used vaccine in the world. Our ability to limit TB is constrained by the simple enormity of the problem with the current case rate being 1,000 times the rate required for elimination of disease. In order to reduce this rate we need to develop rapid diagnostics, short course drugs and an effective vaccine. TB represents a major challenge in vaccine development because we are trying to improve upon an immune response which is largely protective in the majority of individuals. There is also increasing evidence that immunity can be expressed within one lesion of a host and yet fail in another lesion within the same host. We do not know what is going wrong in the failing lesions or in those individuals where latent infection is progressing to active disease. In the work described here we will determine the factors that are critical to the generation of an immune response that is able to maintain protection throughout infection thereby limiting the incidence of disease. This work will help in the design of vaccines. Our working model is that some T cells are protective because they can penetrate and persist within the lesion whereas other vaccine-induced T cells fail because they are excluded from the lesion. Our purpose is to determine what promotes the generation of good T cell populations and what compromises the prolonged function of these T cells within mycobacterial lesions. We will manipulate the T cell and the environment and use confocal imaging, flow cytometry and bacterial burden to determine the functionality of specific subsets of T cells in the lung. By defining these factors we will develop a working model for the generation of T cells capable of functioning in the face of bacterially generated inflammation. This working model can then be integrated with experimental medicine studies and provide a basis for rational vaccine design.

TB represents a major challenge in vaccine development because we do not know constitutes a protective T cell and this is a complex issue in TB as unrestrained T cell responses are pathogenic and T cells must function for prolonged periods in inflammatory lesions to maintain long-term control. We propose that in TB, inflammation limits T cell function in ways that we do not fully understand and that we do not know how to prime T cells that function optimally in inflamed TB lesions, nor do we know what factors limit efficacy of T cells in these lesions. Importantly, we and others have recently determined that antigen-specific CD4 T cells within Mtb lesions exist in novel phenotypic subsets; some express the surface markers PD1 and CD69 and others express the marker KLRG1. The PD-1posCD69pos cells produce IL-2, express the IL-2 and IL-7 receptors, require ICOS and the transcription factor Bcl6 and locate within the parenchyma whereas the KLRG1pos cells express very high levels of the transcription factor T-bet, require IL-27R expression, produce the cytokine IFN and locate within the vasculature. Importantly, when transferred to an Mtb-infected lung, the PD-1posCD69pos population persist while the KLRG1pos population do not and the PD-1posCD69pos CD4 T cells mediate improved bacterial control whereas the KLRG1pos CD4 T cells, while expressing high levels of IFN, do not. Our working model is that protective CD4 T cells penetrate and persist within the mycobacterial lesions but that many vaccine-induced CD4 T cells fail to do this. We hypothesize that TCR-mediated events during priming define the function of T cells and that manipulation of the mycobacterial lesion will permit optimal function of T cells. We will develop a working model of how to generate T cells that function in the context of mycobacterial lesions, which will underpin rational design of vaccine strategies, development of potential correlates of protection and development of host directed therapies.

We all know the power of vaccination and how effective it is in eliminating infectious disease. While we have made excellent progress in developing vaccines for many infectious diseases we have failed to make ones that work against some of the world's most serious public health threats. One such failure is in the development of a vaccine which will eliminate tuberculosis (TB). TB is a major killer and a serious social and economic burden for the vast majority of the world's population. The current case rate is dropping (very slowly) but there is no sign that this disease will be eliminated in our lifetime. What is needed is new diagnostics, new short course drug therapy and a vaccine capable of eliminating the risk of disease in all those vaccinated. The work proposed in this application will provide basic scientific data regarding the best way to induce T cells capable of controlling infection indefinitely (i.e. stopping disease) as well as how to release the capacity of T cells to eliminate the infection (i.e. function effectively). The work is performed in an animal model because we cannot control the experimental parameters sufficiently in human studies in order to gather the type of information needed. However the data sets generated in this work will be actively integrated with human studies in patients and in healthy contacts which will allow us to build a working model of how T cells should be induced and how they can behave during infection.
The principal audience for the work performed here will be other scientists investigating the role of T cells in immune disease, those studying TB in model systems and in humans and those interested in developing/enhancing vaccine delivery systems. While the first two groups are likely publically-funded researchers the latter group includes industry-funded academics.
In the mid to long term the work performed here will be integrated with work from others within the field. This integration will result in a working model of the causes of TB pathogenesis and the development of rational interventions which limit disease occurrence and transmission. The rational interventions to be impacted will be the capacity to design vaccines based on what we know we want (rather than simply guessing) as well as the development/support for host directed therapy pathways which can unleash the power of the T cell response without promoting pathologic consequences.
The beneficiaries of this work are the post-doctoral and technical staff who will obtain training in techniques, intellectual rigour and scientific communication. The Investigator will benefit from being able to pursue her hypotheses and to contribute to the eventual development of an effective vaccine.
Direct effects on TB management in the UK is not a target of this work, however those working with patients in Leicester will be able to benefit from any new developments regarding T cell function identified in the proposed work.
The milestones to be achieved will be:
1. Identification of the role of TCR signal in driving protective T cells - will impact how we vaccinate
2. Identification of the role of IL-2 in development of protective T cells - will impact what we look for when we vaccinate
3. Identification of the role of T cell differentiation in driving protective T cells - will impact how we vaccinate and what we look for following vaccination.
4. Identification of the role of nitric oxide production in regulating T cells- will impact whether we can intervene to allow host responses to work better
5. Identification of the role of T cell intrinsic factors in defining efficacy of T cells- will impact how we vaccinate and whether we can intervene during disease.
6. Determine the functional capacity of T cells with regarding the location and persistence in vivo- will impact whether we can intervene and what to look for as a correlate of protection post vaccination.